CN115572247A - A retinoid K 3 Derivatives and medical use thereof - Google Patents
A retinoid K 3 Derivatives and medical use thereof Download PDFInfo
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Abstract
The invention discloses vitamin K shown as a formula I 3 Derivatives or pharmaceutically acceptable salts or esters thereof, R 1 Selected from the group consisting of hydrogen, fluoro, bromo, methyl, t-butyl, isopropoxy, trifluoromethyl, methoxy, trifluoromethoxy, hydroxy, amino, - (CH) 2 ) n COOH, cyano, nitro; n is an integer of 0 to 2; r is 2 Is a methyl group. Pharmacological experiments prove that the compound or the pharmaceutically acceptable salt or ester thereof can inhibit tumorThe proliferation of tumor cells and the induction of the apoptosis of the tumor cells achieve the aim of resisting tumors, have the effect of resisting tumors, have lower toxicity to normal cells and have better safety. The invention also discloses the vitamin K 3 The derivative or the pharmaceutically acceptable salt or ester thereof can be applied to the preparation of STAT3 inhibitors or the preparation of drugs for preventing and/or treating tumors.
Description
Technical Field
The invention belongs to the field of pharmaceutical chemistry and pharmacotherapeutics, and relates to a vitamin K 3 The derivative and the medical application thereof in preparing STAT3 small molecular inhibitors and preparing tumor treatment medicines.
Background
Signal transduction and transcriptional activators (STATs) are a family of cytoplasmic transcription factor proteins responsible for signal transduction of extracellular cytokines and growth factors and for initiation of transcription of downstream genes. Among them, STAT3 (signal transducer and activator of transcription 3) is a transcription factor involved in the regulation of physiological activities such as cell proliferation, apoptosis, invasion, migration, and immune response, and its abnormal activation plays an important role in the development of tumors. Currently, abnormally or constitutively activated STAT3 proteins have been observed in many different types of cancers, and the activated STAT3 proteins enter the nucleus to promote the expression of various anti-apoptotic protein genes, thereby supporting the development of tumors. This target has become an important anti-tumor target.
After cytokines or growth factors bind to surface receptors, a cascade of reactions occurs through the JAK-STAT3 pathway. The JAK kinase phosphorylates pTyr705 residues of STAT3 monomers, and the two phosphorylated STAT3 monomers bind at pTyr705-SH2 domains and form a dimerization complex of STAT3, which then enters the nucleus of the cell, inducing expression of the relevant tumor genes, so that the pTyr705-SH2 domains play a key role in the entire pathway.
However, the existing small molecule SH2 domain inhibitors have the dilemma of insufficient activity or no statistical difference compared with positive control drugs. Therefore, designing and synthesizing novel small molecule SH2 structural domain inhibitors has an important effect on blocking JAK-STAT3 cell channels.
Disclosure of Invention
The SH2 domain of STAT3 plays a key role in activating recruitment of STAT3 and formation of STAT3 homodimers and formation of STAT3/DNA complexes. The object of the present invention is to provide a potent STAT3 inhibitor against the SH2 domain of STAT 3.
The purpose of the invention is realized by the following technical scheme:
vitamin K with the structure shown as formula I 3 Derivative or a pharmaceutically acceptable salt or ester thereof:
wherein R is 1 Selected from hydrogen, halogen, C1-C4 alkyl, halogen substituted C1-C4 alkyl, hydroxyl, C1-C3 alkoxy, halogen substituted C1-C4 alkoxy, cyano, nitro, amino, - (CH) 2 ) n COOH, aromatic, five-membered or six-membered saturated or unsaturated heterocycle containing 1-2 heteroatoms; n is an integer of 0 to 2; the heteroatom is selected from N, O and S;
R 2 selected from hydrogen, halogen, amino, methylamino, ethylamino, C1-C3 alkyl, C1-C3 alkoxy.
Preferably, R 1 Selected from hydrogen, fluoro, bromo, methyl, t-butyl, isopropoxy, trifluoromethyl, methoxy, trifluoromethoxy, hydroxy, amino, - (CH) 2 ) n COOH, cyano, nitro; n is an integer of 0 to 2; r 2 Is methyl.
More preferably, R 1 Selected from fluoro, trifluoromethyl, methoxy, - (CH) 2 ) n COOH, cyano, nitro; n is an integer of 0 to 2; r is 2 Is a methyl group.
Halogen means fluorine, chlorine, bromine or iodine.
In particular, the vitamin K 3 The derivative is selected from:
as the most preferable technical solution of the present invention,vitamin K 3 The structural formula of the derivative is as follows:
chemical name: 2- (3- ((3-methyl-1, 4-dioxo-8-sulfonamido-1, 4-dihydronaphthalen-2-yl) methyl) phenyl) acetic acid;
chemical name: 3- ((3-methyl-1, 4-dioxo-8-sulfonylamino-1, 4-dihydronaphthalen-2-yl) methyl) benzoic acid.
The vitamin K 3 The pharmaceutically acceptable salt of the derivative is sodium salt and hydrochloride.
The vitamin K 3 The pharmaceutically acceptable ester of the derivative is methyl ester, ethyl ester or tert-butyl ester.
Pharmacological experiments prove that the vitamin K provided by the invention 3 The derivative can achieve the purpose of resisting tumor by inhibiting the proliferation of tumor cells and inducing the apoptosis of the tumor cells, has the effect of resisting tumor, and has lower toxicity to normal cells. Especially, the compounds CH3-3 and CH3-10 have strong growth inhibition effect on lung cancer cells A549, and have better safety.
Another object of the present invention is to provide said vitamin K 3 Use of a derivative or a pharmaceutically acceptable salt or ester thereof in the preparation of a STAT3 inhibitor.
Another object of the present invention is to provide said vitamin K 3 The derivative or the pharmaceutically acceptable salt or ester thereof can be used for preparing the medicine for preventing and/or treating the tumor.
The tumor is lung cancer.
Another object of the present invention is to provide a pharmaceutical composition comprising a therapeutically effective amount of vitamin K 3 A derivative or a pharmaceutically acceptable salt or ester thereof.
Drawings
FIG. 1 is the IC of compound CH3-3 on A549 cells 50 。
FIG. 2 shows IC of compound CH3-9 on A549 cells 50 。
FIG. 3 shows the survival rate of MCF-10A cells treated with 10. Mu.M of compounds CH3-1 to CH 3-9.
Detailed Description
To further illustrate the technical solution of the present invention, a series of examples are given below, which are purely illustrative and are only intended to be a specific description of the present invention, and should not be interpreted as a limitation of the present invention.
Example 1
1) Preparation of 1-naphthalenesulfonamides
Adding 1-naphthalene sulfonyl chloride (10g, 21.9mmol) into a 1L round-bottom flask containing 40mL of tetrahydrofuran, stirring, dropwise adding 15mL of ammonia water (the concentration is 25-28%) at the temperature of 0 ℃ into an ice bath, after dropwise adding, carrying out thin-layer chromatography tracking detection reaction, after the reaction is finished, distilling out an organic solvent and ammonia gas decomposed by the ammonia water under reduced pressure, separating out a solid, filtering, and drying in vacuum to obtain 1-naphthalene sulfonamide (8.70 g, the yield is 96.7%), wherein the compound is directly used for the next reaction without further purification.
1 H NMR(400MHz,DMSO-d 6 )δ8.65(d,J＝8.3Hz,1H,Ar-H),8.20(d,J＝8.2Hz,1H,Ar-H),8.17–8.06(m,2H,Ar-H),7.75–7.69(m,1H,Ar-H),7.69–7.68(m,1H,Ar-H),7.67(d,J＝3.9Hz,2H,NH 2 ),7.63(d,J＝7.9Hz,1H,Ar-H).
2) Preparation of 5, 8-dioxo-dihydronaphthalene-1-sulfonamides
Dissolving anhydrous ceric sulfate (160g, 677.45mmol) in 750mL of 2mol/L dilute sulfuric acid, and controlling the temperature at 65 ℃; adding 1-naphthalene sulfonamide (8.70g, 41.98mmol) into a 500mL round bottom flask containing 200mL acetonitrile, controlling the temperature at 65 ℃, stirring, slowly dropwise adding into a ceric sulfate aqueous phase system, timing from the dropwise adding, monitoring by thin-layer chromatography, stopping the reaction after 20 minutes, cooling the reaction liquid, filtering, extracting the filtrate with 1200mL dichloromethane, drying to remove water, performing low-pressure rotary evaporation to obtain a light yellow solid, performing vacuum drying to obtain 5, 8-dioxo-dihydronaphthalene-1-sulfonamide (5.85 g, the yield is 58.43%), and directly using in the next reaction without purification.
1 H NMR(300MHz,DMSO-d 6 )δ8.45(d,J＝9.2Hz,1H,Ar-H),8.28(d,J＝8.9Hz,1H,Ar-H),8.06(t,J＝7.8Hz,1H,Ar-H),7.38(s,2H,NH 2 ),7.23–7.10(m,2H,Ar-H).
3) Synthesis of 6-methyl-5, 8-dioxo-5, 8-dihydronaphthalene-1-sulfonamide
3g of 5, 8-dioxo-dihydronaphthalene-1-sulfonamide and 1.37mL of glacial acetic acid are dissolved in 120mL of a mixed solution of acetonitrile and dichloromethane (the volume ratio of acetonitrile to dichloromethane is 1: 1), 120mL of an aqueous solution containing 233mg of silver nitrate and 6.25g of ammonium persulfate is rapidly added dropwise, the mixture is stirred under reflux at 80 ℃ for 4 hours, and the reaction is followed and monitored by thin layer chromatography. After the reaction, the aqueous phase was extracted with 450mL of dichloro, the organic layer was washed once with water and saturated sodium chloride, respectively, and the organic layer was dried over anhydrous sodium sulfate, filtered, evaporated under reduced pressure to give a tan powdery solid, which was purified by slurrying with methanol to give 6-methyl-5, 8-dioxo-5, 8-dihydronaphthalene-1-sulfonamide (2.6 g, yield 58.56%).
1 H NMR(300MHz,Chloroform-d)δ8.58(d,J＝8.0Hz,1H,Ar-H),8.40(d,J＝7.9Hz,1H,Ar-H),7.92(t,J＝7.8Hz,1H,Ar-H),6.93(s,1H,Ar-H),5.96(s,2H,NH 2 ),2.28(s,3H,CH 3 ).
4) Synthesis of 7- (3-methoxybenzyl) -6-methyl-5, 8-dioxo-5, 8-dihydronaphthalene-1-sulfonamide (Compound CH 3-1)
300mg of 6-methyl-5, 8-dioxo-5, 8-dihydronaphthalene-1-sulfonamide and 1.59mmol of m-methoxyphenylacetic acid were dissolved in 30mL of a mixed solution of acetonitrile and dichloromethane (the volume ratio of acetonitrile to dichloromethane is 1), an aqueous solution of 13.52mg of silver nitrate and 363.28mg of ammonium persulfate was rapidly added dropwise thereto, and the mixture was stirred under reflux at 80 ℃ for 4 hours and followed by thin layer chromatography to monitor the reaction. After the reaction was completed, the aqueous phase was extracted with 150ml of dichloro-benzene, the organic layer was washed once with water and saturated sodium chloride, respectively, and the organic layer was dried over anhydrous sodium sulfate, suction-filtered, rotary-evaporated under reduced pressure to give a pale yellow powdery solid which was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate =3: 1v/V) to give compound CH3-1 (yield 14.21%).
1 H NMR(300MHz,DMSO-d 6 )δ8.49–8.38(m,1H),8.35–8.23(m,1H),8.01(t,J＝7.9Hz,1H),7.38(s,2H),7.18(t,J＝7.8Hz,1H),6.87–6.69(m,3H),3.96(s,2H),3.71(s,3H),2.18(s,3H)； 13 C NMR(75MHz,DMSO-d 6 )δ184.96,183.58,159.83,146.16,143.72,142.86,139.91,134.33,134.11,133.78,130.57,130.04,129.79,120.95,114.82,111.90,55.40,32.00,13.98。
Example 2
Synthesis of 7- (3-methylbenzyl) -6-methyl-5, 8-dioxo-5, 8-dihydronaphthalene-1-sulfonamide (Compound CH 3-2)
Referring to the synthesis of the compound CH3-1 of example 1, the compound CH3-2 was obtained in a yield of 47.13% as a pale yellow powdery solid by replacing only m-methoxyphenylacetic acid with an equimolar amount of m-methylphenylacetic acid.
1 H NMR(300MHz,DMSO-d 6 )δ8.42(dd,J＝8.0,1.3Hz,1H),8.30(dd,J＝7.8,1.4Hz,1H),8.01(t,J＝7.9Hz,1H),7.39(s,2H),7.15(t,J＝7.5Hz,1H),7.01(dd,J＝13.0,6.2Hz,3H),3.95(s,2H),2.24(s,3H),2.18(s,3H)； 13 C NMR(75MHz,DMSO-d 6 )δ184.97,183.55,146.06,143.94,142.87,138.30,138.15,134.34,134.10,133.79,130.59,129.77,129.39,128.89,127.38,125.88,31.97,21.47,13.98。
Example 3
Synthesis of 2- (3- ((3-methyl-1, 4-dioxo-8-sulfonylamino-1, 4-dihydronaphthalen-2-yl) methyl) phenyl) acetic acid (Compound CH 3-3)
Referring to the synthesis of the compound CH3-1 of example 1, the compound CH3-3 was obtained in 45.76% yield as a pale yellow powdery solid by replacing only m-methoxyphenylacetic acid with equimolar 1, 3-phenylenediacetic acid.
1 H NMR(300MHz,DMSO-d 6 )δ12.30(s,1H),8.42(dd,J＝7.9,1.3Hz,1H),8.30(dd,J＝7.8,1.4Hz,1H),8.01(t,J＝7.9Hz,1H),7.38(s,2H),7.20(d,J＝7.5Hz,1H),7.16–7.01(m,3H),3.98(s,2H),3.52(s,2H),2.18(s,3H)； 13 C NMR(75MHz,DMSO-d 6 )δ184.94,183.54,173.15,146.17,143.81,142.88,138.31,135.77,134.35,134.11,133.80,130.60,129.85,129.76,128.92,127.82,127.06,31.93,13.97。
Example 4
Synthesis of 7- (3-cyanobenzyl) -6-methyl-5, 8-dioxo-5, 8-dihydronaphthalene-1-sulfonamide (Compound CH 3-4)
Referring to the synthesis of the compound CH3-1 of example 1, the compound CH3-4 was obtained in 37.53% yield as a pale yellow powdery solid by replacing only m-methoxyphenylacetic acid with an equimolar amount of 3-cyanophenylacetic acid.
1 H NMR(300MHz,DMSO-d 6 )δ8.42(dd,J＝7.9,1.4Hz,1H),8.28(dd,J＝7.8,1.4Hz,1H),8.00(t,J＝7.9Hz,1H),7.75(d,J＝1.8Hz,1H),7.65(ddt,J＝14.1,8.0,1.4Hz,2H),7.54–7.35(m,3H),4.05(s,2H),2.16(s,3H)； 13 C NMR(75MHz,DMSO-d 6 )δ184.82,183.54,146.91,142.87,142.55,140.26,134.27,134.24,133.97,133.71,132.23,130.63,130.53,130.10,129.87,119.30,111.94,31.70,14.04。
Example 5
Synthesis of 7- (3-trifluoromethoxybenzyl) -6-methyl-5, 8-dioxo-5, 8-dihydronaphthalene-1-sulfonamide (Compound CH 3-5)
Referring to the synthesis of the compound CH3-1 of example 1, the compound CH3-5 was obtained in a yield of 38.56% as a pale yellow powdery solid by replacing only m-methoxyphenylacetic acid with an equimolar amount of 3-trifluoromethoxyphenylacetic acid.
1 H NMR(300MHz,DMSO-d 6 )δ8.42(dd,J＝8.0,1.3Hz,1H),8.29(dd,J＝7.8,1.3Hz,1H),8.01(t,J＝7.9Hz,1H),7.40(d,J＝6.7Hz,3H),7.28(dd,J＝7.7,1.5Hz,2H),7.23–7.16(m,1H),4.05(s,2H),2.17(s,3H)； 13 C NMR(75MHz,DMSO-d 6 )δ184.85,183.56,148.97,148.95,146.66,142.92,142.88,141.30,134.30,134.18,133.76,130.82,130.54,129.83,127.91,121.53,119.15,31.74,13.98。
Example 6
Synthesis of 7- (3-nitrobenzyl) -6-methyl-5, 8-dioxo-5, 8-dihydronaphthalene-1-sulfonamide (Compound CH 3-6)
Referring to the synthesis of the compound CH3-1 of example 1, the compound CH3-6 was obtained in 33.73% yield as a pale yellow powdery solid by replacing only m-methoxyphenylacetic acid with an equimolar amount of 3-nitrophenylacetic acid.
1 H NMR(300MHz,DMSO-d 6 )δ8.42(dd,J＝7.9,1.3Hz,1H),8.30(dd,J＝7.8,1.3Hz,1H),8.14(t,J＝2.0Hz,1H),8.09–7.98(m,2H),7.72(dt,J＝7.8,1.4Hz,1H),7.57(t,J＝7.9Hz,1H),7.39(s,2H),4.14(s,2H),2.20(s,3H)； 13 C NMR(75MHz,DMSO-d 6 )δ184.82,183.56,148.36,146.80,142.90,142.70,140.84,135.67,134.33,134.18,133.79,130.56,130.42,129.83,123.66,121.82,31.76,14.08。
Example 7
Synthesis of 7- (3-bromobenzyl) -6-methyl-5, 8-dioxo-5, 8-dihydronaphthalene-1-sulfonamide (Compound CH 3-7)
Referring to the synthesis of the compound CH3-1 of example 1, the compound CH3-7 was obtained in 36.34% yield as a pale yellow powdery solid by replacing only m-methoxyphenylacetic acid with equimolar 3-bromophenylacetic acid.
1 H NMR(300MHz,DMSO-d 6 )δ8.42(dd,J＝7.9,1.3Hz,1H),8.29(dd,J＝7.8,1.3Hz,1H),8.01(t,J＝7.9Hz,1H),7.48(d,J＝2.2Hz,1H),7.39(d,J＝7.1Hz,3H),7.30–7.18(m,2H),4.00(s,2H),2.17(s,3H)； 13 C NMR(75MHz,DMSO-d 6 )δ184.86,183.54,146.57,143.02,142.87,141.33,134.29,134.18,133.76,131.53,131.10,130.56,129.83,129.66,127.92,122.29,31.72,14.03。
Example 8
Synthesis of 7- (3-trifluoromethylbenzyl) -6-methyl-5, 8-dioxo-5, 8-dihydronaphthalene-1-sulfonamide (Compound CH 3-8)
Referring to the synthesis of the compound CH3-1 of example 1, the compound CH3-8 was obtained in 37.20% yield as a pale yellow powdery solid by replacing only m-methoxyphenylacetic acid with an equimolar amount of 3-trifluoromethylphenylacetic acid.
1 H NMR(300MHz,DMSO-d 6 )δ8.42(dd,J＝8.0,1.3Hz,1H),8.29(dd,J＝7.8,1.3Hz,1H),8.01(t,J＝7.9Hz,1H),7.66(d,J＝2.2Hz,1H),7.60–7.47(m,3H),7.39(s,2H),4.10(s,2H),2.18(s,3H)； 13 C NMR(75MHz,DMSO-d 6 )δ184.85,183.60,146.67,142.95,142.88,140.04,134.30,134.20,133.77,132.89,130.55,130.02,129.84,129.43,126.49,125.56,125.51,123.54,31.89,14.04。
Example 9
Synthesis of 7- (3-fluorobenzyl) -6-methyl-5, 8-dioxo-5, 8-dihydronaphthalene-1-sulfonamide (Compound CH 3-9)
Referring to the synthesis of the compound CH3-1 of example 1, the compound CH3-9 was obtained in 39.87% yield as a pale yellow powdery solid except that m-methoxyphenylacetic acid was replaced with equimolar 3-fluorophenylacetic acid.
1 H NMR(300MHz,DMSO-d 6 )δ8.42(dd,J＝7.9,1.3Hz,1H),8.29(dd,J＝7.8,1.3Hz,1H),8.01(t,J＝7.9Hz,1H),7.44–7.27(m,3H),7.15–6.97(m,3H),4.01(s,2H),2.17(s,3H)； 13 C NMR(75MHz,DMSO-d 6 )δ184.88,183.54,164.36,161.14,146.57,143.07,142.86,141.39,141.29,134.29,134.17,133.76,130.86,130.75,130.56,129.83,124.96,124.92,115.76,115.48,113.66,113.39,31.76,13.99。
Example 10
Synthesis of 3- ((3-methyl-1, 4-dioxo-8-sulfonylamino-1, 4-dihydronaphthalen-2-yl) methyl) benzoic acid (Compound CH 3-10)
Referring to the synthesis of the compound CH3-1 of example 1, the compound CH3-10 was obtained in a yield of 40.25% as a pale yellow powdery solid by replacing only m-methoxyphenylacetic acid with an equimolar amount of 3-carboxymethylphenylacetic acid.
1 H NMR(300MHz,DMSO-d 6 )δ12.96(s,1H),8.42(d,J＝7.9Hz,1H),8.30(d,J＝7.7Hz,1H),8.01(t,J＝7.9Hz,1H),7.77(d,J＝7.6Hz,2H),7.49(d,J＝7.7Hz,1H),7.44–7.30(m,3H),4.06(s,2H),2.20(s,3H)； 13 C NMR(75MHz,DMSO-d 6 )δ184.90,183.55,167.70,146.33,143.51,142.91,139.00,134.38,134.08,133.84,133.36,131.45,130.59,129.78,129.72,129.32,127.77,31.92,14.03。
Example 11
Evaluation of antitumor cell proliferation Activity of Compounds CH3-1 to CH3-10
1.1 testing the inhibitory activity of compounds CH 3-1-CH 3-10 and compound LY-17 on tumor cells by MTT method
Non-small cell lung cancer cells (a 549) were purchased from shanghai biochemical and cell biology institute cell banks of chinese academy of sciences (shanghai, china). Non-small cell lung carcinoma cells (A549) were cultured in DMEM medium containing 50. Mu.g/mL penicillin, 50. Mu.g/mL streptomycin, and 10% fetal bovine serum. The cells were incubated at 37 ℃ in a tissue culture flask with 5% CO 2 Grown to 80% confluence, then trypsinized and cleaved with 1 × Trypsin-Versene.
Test compounds: compounds CH3-1 to CH3-10; positive control: compound LY-17 (WO 2014028909A 1):
preparing a liquid medicine: test compounds and positive controls were taken, and a 10mM compound stock solution was prepared using biological-grade 99.9% DMSO, and the compounds were diluted with the corresponding medium to obtain a drug solution with a concentration of 20. Mu.M.
MTT test: counting A549 cells after passage, preparing cell suspension according to the density of 3500-4000 cells/hole, uniformly mixing, sucking the cell suspension, inoculating the cell suspension into a 96-well plate, 100 mu L of each hole, adhering the walls overnight, administrating the drug the next day, sucking out the cell culture solution in the 96-well plate, and obtaining an experimental group: media containing different compounds (20 μ M) were added at 100 μ L per well, blank: adding culture medium without medicine into each well at a ratio of 100 μ L; after 72 hours of incubation, the liquid medicine in the 96-well plate was aspirated, 100. Mu.L of a medium containing 10% CCK-8 was added to each well, incubation was performed for 4 hours in the absence of light, the 96-well plate was taken out after completion, and the absorbance of each well was measured by a fluorescence microplate reader at a detection wavelength of 470nm and a reference wavelength of 630nm.
Growth inhibition rate of tumor cells: proliferation inhibition ratio (%) = (1-A) Experimental group /A Blank group )×100％
Table 1 shows the results of the inhibitory activity of the compounds on a549 cells, as seen: the 10 compounds have proliferation inhibition effect on A549 cells, particularly, the inhibition activity of the compounds CH3-1, CH3-3, CH3-4, CH3-6, CH3-9 and CH3-10 on the A549 cells is obvious and is obviously better than that of a positive drug LY-17 or close to that of the positive drug LY-17, and particularly, the compounds CH3-3 and CH3-10 can completely inhibit the tumor growth (> 95%) at the concentration of 20 mu m.
TABLE 1 inhibition of A549 cells by Compounds
1.2 testing of IC of Compounds CH3-3, CH3-9 Using MTT method 50 (half inhibitory concentration) value
MTT test: counting A549 cells after passage, preparing cell suspension according to the density of 3500-4000/well, mixing uniformly, sucking the cell suspension, inoculating the cell suspension into a 96-well plate, 100 mu L per well, attaching overnight, dosing the mixture on the next day, preparing 10mmol of compound mother liquor by adopting 99.9-percent DMSO (biological grade), diluting the compound by using corresponding culture medium to the final concentration of 0, 0.125, 0.25, 0.5, 1, 2, 4, 8, 16 and 32 mu M to obtain 10 concentration gradients, sucking the cell culture solution in the 96-well plate, adding culture medium containing compounds with different concentrations into each well according to 100 mu L per well, and performing blank group: adding culture medium without medicine into each well at a volume of 100 μ L; after 72 hours of incubation, the solution was aspirated from the 96-well plate, and 100. Mu.L of a medium containing 10% CCK-8 was added to each well, and incubated for 4 hours in the absence of light. And (4) taking out the 96-well plate after the reaction is finished, and measuring the light absorption value of each well by using a fluorescence microplate reader, wherein the detection wavelength is 470nm, and the reference wavelength is 630nm.
Growth inhibition rate of tumor cells: proliferation inhibition ratio (%) = (1-A) Experimental group /A Blank group )×100％
FIG. 1 shows the results of the inhibitory activity of CH3-3 compound on A549 cells, IC 50 At 5.828. Mu.M.
FIG. 2 shows the results of the inhibitory activity of compound CH3-9 on A549 cells, IC 50 The (half inhibitory concentration) was 8.451. Mu.M.
Example 12
Evaluation of toxicity of Compounds CH3-1 to CH3-9 on Normal cells
2.1 testing toxicity of compounds CH 3-1-CH 3-9 and compound LY-17 to normal cells by MTT method
Human normal mammary epithelial cells (MCF-10A) were purchased from Shanghai institute of biochemistry and cell biology, cell Bank, china, shanghai, academy of sciences. Human normal mammary epithelial cells (MCF-10A) were cultured in DMEM medium containing 50. Mu.g/mL penicillin, 50. Mu.g/mL streptomycin, and 10% fetal bovine serum. The cells were incubated at 37 ℃ in a tissue culture flask with 5% CO 2 Grown to 80% confluence, then trypsinized and cleaved with 1 × Trypsin-Versene.
Test compounds: compounds CH3-1 to CH3-9; positive control: compound LY-17.
Preparing a liquid medicine: test compounds and positive controls were taken, and a 10mM compound stock solution was prepared using biological-grade 99.9% DMSO, and the compounds were diluted with the corresponding medium to obtain a drug solution with a concentration of 10. Mu.M.
MTT test: counting MCF-10A cells after passage, preparing cell suspension according to the density of 3500-4000 cells/hole, uniformly mixing, sucking the cell suspension, inoculating the cell suspension into a 96-well plate, 100 mu L of each hole, attaching to the wall overnight, feeding the drug the next day, sucking out cell culture solution in the 96-well plate, and performing experimental group: media containing different compounds (10 μ M) were added at 100 μ L per well, blank: adding culture medium without medicine into each well at a volume of 100 μ L; after 72 hours of incubation, the liquid medicine in the 96-well plate was aspirated, 100. Mu.L of a medium containing 10% CCK-8 was added to each well, incubation was performed for 4 hours in the absence of light, the 96-well plate was taken out after completion, and the absorbance of each well was measured by a fluorescence microplate reader at a detection wavelength of 470nm and a reference wavelength of 630nm.
Growth inhibition rate of tumor cells: proliferation inhibition rate (%) = (1-A) Experimental group /A Blank group )×100％
FIG. 3 shows the combination at 10. Mu.MThe toxicity result of the compound on MCF-10A cells shows that the survival rate of the MCF-10A cells under 9 compound treatments is obviously higher than that of a control LY-17, which indicates that the vitamin K of the invention 3 The derivative has better safety.
Claims (10)
1. Vitamin K with the structure shown as formula I 3 Derivative or a pharmaceutically acceptable salt or ester thereof:
wherein R is 1 Selected from hydrogen, halogen, C1-C4 alkyl, halogen substituted C1-C4 alkyl, hydroxyl, C1-C3 alkoxy, halogen substituted C1-C4 alkoxy, cyano, nitro, amino, - (CH) 2 ) n COOH, aromatic, five-membered or six-membered saturated or unsaturated heterocycle containing 1-2 heteroatoms; n is an integer of 0 to 2; the heteroatom is selected from N, O and S;
R 2 selected from hydrogen, halogen, amino, methylamino, ethylamino, C1-C3 alkyl, C1-C3 alkoxy.
2. Vitamin K in accordance with claim 1 3 A derivative characterized by: r 1 Selected from the group consisting of hydrogen, fluoro, bromo, methyl, t-butyl, isopropoxy, trifluoromethyl, methoxy, trifluoromethoxy, hydroxy, amino, - (CH) 2 ) n COOH, cyano, nitro; n is an integer of 0 to 2; r is 2 Is a methyl group.
3. Vitamin K in accordance with claim 1 3 A derivative characterized by: r 1 Selected from fluorine, trifluoromethyl, methoxy, - (CH) 2 ) n COOH, cyano, nitro; n is an integer of 0 to 2; r 2 Is methyl.
4. Vitamin K in accordance with claim 1 3 A derivative characterized by: vitamin K 3 The derivatives are selected from the following compounds:
5. vitamin K having the structure shown as the following formula 3 Derivative or a pharmaceutically acceptable salt or ester thereof:
6. vitamin K in accordance with one of claims 1 to 5 3 A derivative or a pharmaceutically acceptable salt or ester thereof, characterized in that: the vitamin K is 3 The pharmaceutically acceptable salt of the derivative is sodium salt and hydrochloride, and the vitamin K is 3 The pharmaceutically acceptable ester of the derivative is methyl ester, ethyl ester or tert-butyl ester.
7. Vitamin K according to any one of claims 1 to 5 3 Use of a derivative or a pharmaceutically acceptable salt or ester thereof in the preparation of a STAT3 inhibitor.
8. Vitamin K according to any one of claims 1 to 5 3 The derivative or the pharmaceutically acceptable salt or ester thereof can be used for preparing the medicine for preventing and/or treating the tumor.
9. Use according to claim 8, characterized in that: the tumor is lung cancer.
10. A pharmaceutical composition characterized by: comprising a therapeutically effective amount of vitamin K as claimed in any one of claims 1 to 5 3 A derivative or a pharmaceutically acceptable salt or ester thereof.
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Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20150232434A1 (en) * | 2012-08-16 | 2015-08-20 | Ohio State Innovation Foundation | Stat3 inhibitors and their anticancer use |
| CN106632060A (en) * | 2015-10-30 | 2017-05-10 | 中国药科大学 | N-naphthylalkyl-substituted nitrogen-containing heterocyclic derivatives and preparation method and antitumor application thereof |
| CN108530394A (en) * | 2017-03-06 | 2018-09-14 | 中国科学院成都有机化学有限公司 | A kind of synthesis vitamin K3The method of epoxides |
| CN112939824A (en) * | 2021-02-20 | 2021-06-11 | 中国药科大学 | Compound and medical application thereof in colorectal cancer |
| CN113845476A (en) * | 2021-11-08 | 2021-12-28 | 中国药科大学 | Quinolone derivative and preparation method and application thereof |
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Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20150232434A1 (en) * | 2012-08-16 | 2015-08-20 | Ohio State Innovation Foundation | Stat3 inhibitors and their anticancer use |
| CN106632060A (en) * | 2015-10-30 | 2017-05-10 | 中国药科大学 | N-naphthylalkyl-substituted nitrogen-containing heterocyclic derivatives and preparation method and antitumor application thereof |
| CN108530394A (en) * | 2017-03-06 | 2018-09-14 | 中国科学院成都有机化学有限公司 | A kind of synthesis vitamin K3The method of epoxides |
| CN112939824A (en) * | 2021-02-20 | 2021-06-11 | 中国药科大学 | Compound and medical application thereof in colorectal cancer |
| CN113845476A (en) * | 2021-11-08 | 2021-12-28 | 中国药科大学 | Quinolone derivative and preparation method and application thereof |
Non-Patent Citations (1)
| Title |
|---|
| ZHOUXIANG ZHANG ET AL.: ""The electro-synthesized imprinted PEDOT film as a simple voltammetric sensor for highly sensitive and selective detection of vitamin K3 in poultry drug samples"", SYNTHETIC METALS, vol. 230, pages 79 - 88, XP085113774, DOI: 10.1016/j.synthmet.2017.05.015 * |
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