CN113929639B - Antitumor compound with GSTP1 as target spot, and preparation method and application thereof - Google Patents
Antitumor compound with GSTP1 as target spot, and preparation method and application thereof Download PDFInfo
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Abstract
The invention discloses an antitumor compound taking GSTP1 as a target spot and pharmaceutically acceptable salts thereof, which comprise a compound with a structure shown as a formula I, wherein n =1-3; when R is 1 When is H, R 2 Is aryl or alkyl; when R is 2 When the aryl is selected from phenyl, mono-substituted or di-substituted phenyl, and the substituent is CH 3 、OCH 3 、OCF 3 F, cl or Br, and the substituent is at any position of ortho, meta or para; when R is 2 When it is an alkyl group, it is selected from C 1～4 Dimethylamino radical of straight-chain alkyl, C 1～4 Diethylamino of straight-chain alkyl, C 1～4 Morpholinyl of straight-chain alkyl, C 1～4 Piperidinyl or C of straight-chain alkyl groups 1～4 Pyrrolidinyl of straight chain alkyl; or，R 1 And R 2 Morpholine or piperidyl which forms a cyclic structure with the N atom.
Description
Technical Field
The invention relates to a compound, a preparation method and application thereof, in particular to an antitumor compound taking GSTP1 as a target spot, and a preparation method and application thereof.
Background
Glutathione mercaptotransferase (GSTs) belongs to II metabolic enzymes, is an extremely important exogenous chemical metabolic enzyme, is closely related to the generation and development of various tumors, and plays an important role in the process of cell detoxification. GSTs are a large super gene family, mainly including cytoplasmic, mitochondrial and microsomal families, wherein the cytoplasmic family is the most complex and most closely related to human diseases. The cytoplasm family mainly comprises seven subtypes of alpha, pi, mu, theta, kappa, omega and delta.
GSTP1 (GST pi) has multiple biological functions, and is frequently overexpressed in tumor cells, such as human colon cancer, pancreatic cancer, uterine cancer, gastric cancer, breast cancer, lymphoma, liver cancer, melanoma, osteosarcoma, and the like, but is lower in content in normal cells. Therefore, the GSTP 1-targeting drug plays an important role in tumor cells and has the lowest toxic and side effects on normal cells. Many exogenous chemicals are highly susceptible to the formation of reactive intermediates in biotransformation reactions, which can cause damage to the body by covalently bonding to important components of cellular biological macromolecules. GSTP1 can catalyze the combination of sulfhydryl of Glutathione (GSH) and various electrophilic compounds from in vivo and in vitro sources to form a compound with larger polarity, and multi-drug resistance protein (MRP) and P-glycoprotein (P-gp) can pump the compound out of the body, thereby realizing the detoxification of GSTP 1. Meanwhile, most chemotherapy drugs can be catalyzed by GSTP1 and combined with GSH to form a compound, and the compound is pumped out of the body by multi-drug resistant protein, so that the action time of the drugs in the body is shortened, the anti-tumor effect can not be effectively exerted, and the serious tumor cell multi-drug resistance is caused clinically. c-jun amino terminal kinase (JNK) plays an important role in various physiological and pathological processes such as cell cycle, reproduction, apoptosis and cell stress. Under a non-stress state, GSTP1 and JNK form a compound through protein-protein interaction in a monomer form, so that the JNK is inactivated, and tumor cells are prevented from apoptosis. Under a stress state, GSTP1 and JNK are separated to form a homodimer, JNK can mediate c-jun protein phosphorylation to activate an apoptosis pathway, but when GSTP1 expression is increased, apoptosis is inhibited, and drug resistance is generated in tumor cells. The GSTP1 can effectively promote the apoptosis of tumor cells, so the GSTP1 becomes one of the targets for researching the antitumor drugs.
Currently, GSTP1 inhibitors are mainly advantageous for uric acid (EA) analogs, GSH-conjugates, GSH analogs, NBDHEX (6- (7-nitro-2, 1, 3-benzoxadiazol-4-ylthio) hexanol) and analogs thereof, and the like. NBDHEX is a GSTP1 inhibitor reported by Duvicat university of Italy in 2005, the structure of which is shown as (2) in the following formula, and the structure of the derivative is shown as (3), and the derivative has strong antitumor activity on melanoma and osteosarcoma. Because of the high selectivity to GSTM2 subtype, the targeting to tumor cells is low, and the poor water solubility also hinders the deep research on the tumor cells. GSTM2 protein is expressed in a plurality of non-cancer tissues, and GSTP1 is expressed in a plurality of solid tumors at high level, which can promote the combination of a plurality of antitumor drugs and glutathione, so that the antitumor drugs are excreted from cells, and then drug resistance is generated. The inhibition of GSTP1 protein can effectively activate JNK pathway and promote tumor cell apoptosis.
Wherein n =1, 2, 3.
Disclosure of Invention
The purpose of the invention is as follows: the invention aims to utilize hydroxyl in the structure of known compound NBDHEX to react with naphthenic acid anhydride to introduce carboxyl, and then introduce amine with different substituent groups through esterification reaction to obtain a compound with anti-tumor effect so as to obtain a high-efficiency low-toxicity medicament; the invention also aims to provide a preparation method of the compounds and discloses application of the compounds as GSTP1 inhibitors in preparing medicaments for treating lung cancer, melanoma and osteosarcoma.
The technical scheme is as follows: the antitumor compound taking GSTP1 as a target and pharmaceutically acceptable salts thereof comprise a compound with a structure shown in a formula I:
wherein, in formula I, n =1-3;
when R is 1 When is H, R 2 Is aryl or alkyl; when R is 2 When the aryl is phenyl, mono-substituted or di-substituted phenyl, the substituent is CH 3 、OCH 3 、OCF 3 F, cl or Br, and the substituent can be at any position of ortho, meta or para; when R is 2 When it is an alkyl group, it may be C 1～4 Dimethylamino radical of straight-chain alkyl, C 1～4 Diethylamino of straight-chain alkyl, C 1～4 Morpholinyl of straight-chain alkyl, C 1～4 Piperidinyl or C of straight-chain alkyl groups 1～4 Pyrrolidinyl of straight chain alkyl;
or, R 1 And R 2 Morpholine or piperidine which may form a cyclic structure with the N atom.
Preferably, the GSTP 1-targeted antitumor compound and the pharmaceutically acceptable salt thereof are selected from the following compounds 4a-4t:
TABLE 1 structures of representative Compounds 4a-4t
The preparation method of the antitumor compound taking GSTP1 as the target point and the pharmaceutically acceptable salt thereof comprises the following steps:
TBTU stands for the condensing agent tetrafluoroboric acid-2- (1H-benzotriazol-1-yl) -1, 3-tetramethyluronium, et 3 N represents triethylamine, and DMF represents solvent N, N-dimethylformamide.
Further, the preparation method of the antitumor compound taking GSTP1 as the target spot and the pharmaceutically acceptable salt thereof specifically comprises the following steps:
dissolving compound 3 and TBTU in anhydrous DMF, stirring at room temperature, adding Et 3 And N, adding different substituted secondary amines, stirring the reaction solution at 30-40 ℃ for 1-3h, then removing the solvent under reduced pressure, and separating the concentrated solution by silica gel column chromatography, wherein the eluent is a mixed solvent of dichloromethane and methanol to obtain a yellow or brown solid product, wherein the compounds 4o and 4r are oily substances.
Further, in the preparation method of the antitumor compound taking GSTP1 as the target and the pharmaceutically acceptable salt thereof, the preparation of the compound 3 is carried out according to the following reaction formula:
formula III wherein n =1-3; DMAP for 4-dimethylaminopyridine and DCM for CH 2 Cl 2 。
Further, the preparation method of the antitumor compound taking GSTP1 as the target point and the pharmaceutically acceptable salt thereof comprises the following steps:
1) Synthesis of compound 2 (according to us patent: US 8796317): dissolving compound 1 named 4-chloro-7-nitro-2, 1, 3-benzoxadiazole in neutral ethanol and potassium phosphate buffer solution, stirring at room temperature for 5-15min, adding 6-mercapto-1-hexanol, reacting at room temperature for 20-28h, and regulating with KOH to keep the reaction neutral; after the reaction is finished, adding 3-bromopyruvic acid to consume unreacted 6-mercapto-1-hexanol, stirring for 1-2h, filtering, and washing a filter cake with water to obtain a dark yellow solid compound 2;
2) Synthesis of Compound 3 (reference patent application No.: 201811396573.5): dissolving 2 in CH 2 Cl 2 Adding naphthenic dianhydride and DMAP, reacting overnight at 40-50 ℃, cooling to room temperature, concentrating the reaction solution, and performing column chromatography separation to obtain a yellow product 3, wherein the eluent is a mixed solvent of dichloromethane and methanol.
A pharmaceutical composition, comprising an antitumor compound targeting GSTP1 of formula I or any one of compounds 4a-4t, and pharmaceutically acceptable salts thereof.
The antitumor compound taking GSTP1 as a target point and the pharmaceutically acceptable salt thereof are applied to a GSTP1 inhibitor.
The antitumor compound taking GSTP1 as a target point and the pharmaceutically acceptable salt thereof are applied to a GSTM2 inhibitor.
The antitumor compound taking GSTP1 as a target spot and pharmaceutically acceptable salts thereof are applied to the preparation of medicines for treating lung cancer, melanoma and osteosarcoma.
Has the beneficial effects that: the invention utilizes the hydroxyl in the structure of known compound NBDHEX to react with naphthenic acid anhydride to introduce carboxyl, and then introduces amine with different substituent groups through esterification reaction to obtain a novel compound with anti-tumor effect. The selective inhibition of glutathione transferase and in vitro antitumor activity test show that the compound of the present invention has obvious inhibition effect on some tumor cells and may be used in preparing medicine.
Detailed Description
Synthesis of compound 2 according to us patent: US8796317, the synthesis of compound 3 refers to the invention patent with the application number of 201811396573.5. Reactant 1 was purchased from Shanghai Aladdin Biotechnology Ltd. The molecular structure of the compound prepared by the method is determined by nuclear magnetic hydrogen spectrum, carbon spectrum and high-resolution mass spectrum.
Example 1
Preparation of Compound 2 (NBDHEX) and 3
(1) Preparation of Compound 2
4.0g (20 mmol) of Compound 1 (4-chloro-7-nitro-2, 1, 3-benzoxadiazole) was dissolved in a buffer solution of ethanol and potassium phosphate at pH 7.0, stirred at room temperature for 10min, then 10.7g (40 mmol) of 6-mercapto-1-hexanol was added, and the mixture was reacted at room temperature for 24h and adjusted with 1M KOH to keep the solution neutral. After completion of the reaction, 5.0g (30 mmol) of 3-bromopyruvic acid was added, stirred for 1 hour, filtered, and the filter cake was washed with water (20 mL. Times.3) to give Compound 2 as a dark yellow solid.
1 H NMR(600MHz,CDCl 3 )δ8.39(d,J＝7.9Hz,1H),7.15(d,J＝7.9Hz,1H),3.65(t,J＝6.4Hz,2H),3.26(t,J＝7.4Hz,2H),1.88–1.84(m,2H),1.61–1.55(m,4H),1.47–1.42(m,2H).
HRMS(ESI)m/z calcd for C 12 H 15 N 3 O 4 S[M+Na] + 320.0675,found 320.0684.
(2) Preparation of Compound 3
3.0g (10 mmol) of 2 are dissolved in CH 2 Cl 2 Then, 3g (30 mmol) of succinic anhydride (n = 1) and 3.7g (30 mmol) of DMAP were added, and the mixture was reacted overnight at 45 ℃, cooled to room temperature, concentrated, and subjected to column chromatography to obtain a yellow product 3, which was a mixed solvent of dichloromethane and methanol 10.
1 H NMR(600MHz,CDCl 3 )δ8.41(d,J＝7.9Hz,1H),7.17(d,J＝7.9Hz,1H),4.11(t,J＝6.5Hz,2H),3.28(t,J＝7.3Hz,2H),2.68(t,J＝6.7Hz,2H),2.62–2.59(m,2H),1.88–1.83(m,2H),1.68–1.64(m,2H),1.59–1.54(m,2H),1.46–1.40(m,2H).
HRMS(ESI)m/z calcd for C 16 H 19 N 3 O 7 S[M+Na] + 420.0836,found 420.0858.
Example 2
(II) preparation of target Compound
EXAMPLE 1 preparation of Compound 4a
189.6mg (0.5 mmol) of Compound 3 and 192.7mg (0.6 mmol) of TBTU were dissolved in 10mL of anhydrous DMF, stirred at room temperature for 5min, and 65.8mg (0.65 mmol) of Et was added 3 N, stirring was continued for 2min, then 55.9mg (0.6 mmol) of aniline were added and the reaction was carried out at 35 ℃ for 2h. The reaction solution was concentrated, and the concentrate was separated by silica gel column chromatography, and the eluent was a mixed solvent of dichloromethane and methanol (30: 69.5 percent.
1 H NMR(600MHz,DMSO–d 6 ):δ9.96(s,1H),8.54(d,J＝7.9Hz,1H),7.55(d,J＝7.8Hz,2H),7.46(d,J＝8.0Hz,1H),7.26(t,J＝7.9Hz,2H),6.99(t,J＝7.4Hz,1H),4.03(t,J＝6.5Hz,2H),3.12(t,J＝7.4Hz,2H),2.59(s,4H),1.74–1.69(m,2H),1.60–1.55(m,2H),1.48–1.43(m,2H),1.39–1.34(m,2H)； 13 C NMR(150MHz,DMSO–d 6 ):δ172.9,170.3,149.6,143.1,140.5,139.7,132.8,132.5,129.1,123.4,122.5,119.3,64.3,31.4,31.0,29.2,28.5,28.3,27.8,25.3.
HRMS(ESI)m/z calcd for C 22 H 25 N 4 O 6 S[M+H] + 473.1489,found 473.1498.
EXAMPLE 2 preparation of Compound 4b
Prepared as described in example 1, substituting 2-fluoroaniline for aniline, to give the yellow product in 71.3% yield.
1 H NMR(600MHz,CDCl 3 ):δ8.40[d,J＝7.9Hz,1H),8.25(t,J＝7.9Hz,1H),7.65(s,1H),7.13(d,J＝7.9Hz,1H),7.08–6.99(m,3H),4.14(t,J＝6.5Hz,2H),3.25(t,J＝7.4Hz,2H),2.76–2.71(m,4H),1.85–1.80(m,2H),1.69–1.65(m,2H),1.57–1.52(m,2H),1.46–1.41(m,2H)； 13 C NMR(150MHz,CDCl 3 ):δ172.8,169.7,153.1(d,J＝241.5Hz),149.1,142.4,141.8,132.4,130.7,126.2,124.5,124.3,121.6,120.3,114.8,64.6,32.0,31.5,29.3,28.4,28.3,27.7,25.3.
HRMS(ESI)m/z calcd for C 22 H 24 FN 4 O 6 S[M+H] + 491.1395,found 491.1388.
EXAMPLE 3 preparation of Compound 4c
Prepared as described in example 1, substituting 2-chloroaniline for aniline, gave a light yellow product in 81.1% yield.
1 H NMR(600MHz,DMSO–d 6 ):δ9.52(s,1H),8.54(d,J＝8.1Hz,1H),7.70(d,J＝7.9Hz,1H),7.47(d,J＝8.0Hz,1H),7.45–7.43(m,1H),7.29(t,J＝7.3Hz,1H),7.14(t,J＝7.4Hz,1H),4.04(t,J＝6.5Hz,2H),3.33–3.31(m,2H),2.69–2.67(m,2H),2.60(t,J＝6.6Hz,2H),1.76–1.71(m,2H),1.6–1.56(m,2H),1.49–1.46(m,2H),1.40–1.35(m,2H)； 13 C NMR(150MHz,DMSO–d 6 ):δ172.7,170.7,149.6,143.1,140.5,135.4,132.8,132.5,129.9,127.7,126.6,126.4,126.3,122.6,64.2,31.0,30.9,29.3,28.5,28.3,27.8,25.3.
HRMS(ESI)m/z calcd for C 22 H 24 ClN 4 O 6 S[M+H] + 507.1100,found 507.1120.
EXAMPLE 4 preparation of Compound 4d
Prepared as described in example 1, substituting 2-methylaniline for aniline, gave a pale yellow solid in 62.3% yield.
1 H NMR(600MHz,DMSO–d 6 ):δ9.31(s,1H),8.53(d,J＝7.9Hz,1H),7.47(d,J＝8.0Hz,1H),7.36(d,J＝7.9Hz,1H),7.16(d,J＝7.4Hz,1H),7.12(t,J＝7.5Hz,1H),7.03(t,J＝7.3Hz,1H),4.04(t,J＝6.6Hz,2H),3.33(t,J＝7.4Hz,2H),2.64–2.58(m,4H),2.17(s,3H),1.76–1.71(m,2H),1.61–1.56(m,2H),1.50–1.45(m,2H),1.40–1.35(m,2H)； 13 C NMR(150MHz,DMSO–d 6 ):δ172.9,170.2,149.6,143.1,140.5,136.8,132.8,132.5,132.0,130.7,126.3,125.4,125.3,122.6,64.2,31.0,30.8,29.5,28.5,28.3,27.8,25.3,18.3.
HRMS(ESI)m/z calcd for C 23 H 27 N 4 O 6 S[M+H] + 487.1645,found 487.1649.
EXAMPLE 5 preparation of Compound 4e
Prepared as described in example 1, substituting 2-methoxyaniline for aniline, gave an orange solid in 75.5% yield.
1 H NMR(600MHz,DMSO–d 6 ):δ9.12(s,1H),8.54(d,J＝7.2Hz,1H),7.93(d,J＝6.0Hz,1H),7.46(d,J＝7.3Hz,1H),6.99(s,2H),6.84(s,1H),4.02(s,2H),3.81(s,3H),3.33(d,J＝9.9Hz,2H),2.68(s,2H),2.56(s,2H),1.77–1.68(m,2H),1.62–1.54(m,2H),1.51–1.43(m,2H),1.40–1.34(m,2H)； 13 C NMR(150MHz,DMSO–d 6 ):δ172.9,170.5,149.7,149.6,143.1,140.5,132.8,132.5,127.8,124.5,122.5,122.0,120.6,111.5,64.2,56.1,31.331.0,29.4,28.5,28.3,27.8,25.3.
HRMS(ESI)m/z calcd for C 23 H 27 N 4 O 7 S[M+H] + 503.1595,found 503.1590.
EXAMPLE 6 preparation of Compound 4f
Prepared as described in example 1 using 3-chloroaniline instead of aniline, gave a light yellow solid in 75.5% yield.
1 H NMR(600MHz,DMSO–d 6 ):δ10.15(s,1H),8.54(d,J＝8.5Hz,1H),7.77(s,1H),7.46(d,J＝8.0Hz,1H),7.38(d,J＝8.2Hz,1H),7.29(t,J＝8.1Hz,1H),7.07(dd,J＝7.9,1.2Hz,1H),4.03(t,J＝6.5Hz,2H),3.32(t,J＝7.4Hz,2H),2.62–2.56(m,4H),1.74–1.69(m,2H),1.60–1.55(m,2H),1.48–1.43(m,2H),1.39–1.34(m,2H)； 13 C NMR(150MHz,DMSO–d 6 ):δ172.7,170.7,149.6,143.1,141.1,140.5,133.5,132.7,132.5,130.8,123.1,122.5,118.8,117.6,64.3,31.4,30.9,29.1,28.5,28.3,27.8,25.3.
HRMS(ESI)m/z calcd for C 22 H 24 ClN 4 O 6 S[M+Na] + 507.1100,found 507.1109.
EXAMPLE 7 preparation of 4g Compound
Prepared as described in example 1, substituting 4-fluoroaniline for aniline, to give a yellow solid in 75.5% yield.
1 H NMR(600MHz,CDCl 3 ):δ8.40(d,J＝6.5Hz,1H),7.73(s,1H),7.44–7.42(m,2H),7.14(d,J＝6.4Hz,1H),6.96(t,J＝8.2Hz,2H),4.12(t,J＝6.2Hz,2H),3.25(t,J＝6.7Hz,2H),2.73(s,2H),2.66(s,2H),1.87–1.78(m,2H),1.69–1.62(m,2H),1.58–1.49(m,2H),1.47–1.38(m,2H)； 13 C NMR(150MHz,CDCl 3 ):δ173.2,169.7,160.0(d,J＝241.5Hz),149.1,142.4,141.9,133.8,132.4,130.8,121.5,121.4,120.3,115.6,115.4,64.6,31.8,31.6,29.3,28.3,28.2,27.6,25.3.
HRMS(ESI)m/z calcd for C 22 H 24 FN 4 O 6 S[M+H] + 491.1395,found 491.1389.
EXAMPLE 8 preparation of Compound 4h
Prepared as described in example 1, substituting 4-bromoaniline for aniline, to give a yellow solid in 70.2% yield.
1 H NMR(600MHz,DMSO–d 6 ):δ10.10(s,1H),8.54(d,J＝7.9Hz,1H),7.52(d,J＝8.5Hz,2H),7.46(d,J＝7.9Hz,1H),7.42(d,J＝8.5Hz,2H),4.03(t,J＝6.2Hz,2H),3.31(t,J＝7.5Hz,2H),2.59(s,4H),1.74–1.68(m,2H),1.60–1.54(m,2H),1.48–1.42(m,2H),1.39–1.32(m,2H)； 13 C NMR(150MHz,DMSO–d 6 ):δ172.8,170.5,149.6,143.1,140.5,139.0,132.7,132.5,131.9,122.5,121.2,114.9,64.2,31.4,31.0,29.1,28.5,28.3,27.8,25.3.
HRMS(ESI)m/z calcd for C 22 H 24 BrN 4 O 6 S[M+H] + 533.0576,found 533.0580.
Example 9 preparation of Compound 4i
Prepared as described in example 1, substituting 4-methylaniline for aniline, gave a yellow solid in 83.2% yield.
1 H NMR(600MHz,DMSO–d 6 ):δ9.85(s,1H),8.53(d,J＝8.0Hz,1H),7.45(d,J＝8.0Hz,1H),7.42(d,J＝8.3Hz,2H),7.04(d,J＝8.3Hz,2H),4.03(t,J＝6.5Hz,2H),3.31(t,J＝7.4Hz,2H),2.57(s,4H),2.20(s,3H),1.74–1.69(m,2H),1.60–1.55(m,2H),1.48–1.43(m,2H),1.39–1.34(m,2H)； 13 C NMR(150MHz,DMSO–d 6 ):δ172.9,170.0,149.6,143.1,140.5,137.2,132.8,132.5,132.2,129.4,122.5,119.3,64.2,31.3,31.0,29.3,28.5,28.3,27.8,25.3,20.9.
HRMS(ESI)m/z calcd for C 23 H 27 N 4 O 6 S[M+H] + 487.1645,found 487.1640.
EXAMPLE 10 preparation of Compound 4j
Prepared as described in example 1 using 4-methoxyaniline instead of aniline to give a yellow solid in 81.0% yield.
1 H NMR(600MHz,DMSO–d 6 ):δ9.81(s,1H),8.54(d,J＝8.0Hz,1H),7.46–7.44(m,3H),6.82–6.80(m,2H),4.03(t,J＝6.5Hz,2H),3.67(s,3H),3.32(t,J＝7.4Hz,2H),2.57(s,4H),1.74–1.69(m,2H),1.60–1.55(m,2H),1.48–1.43(m,2H),1.39–1.34(m,2H)； 13 C NMR(150MHz,DMSO–d 6 ):δ172.9,169.7,155.4,149.6,143.1,140.5,132.9,132.8,132.5,122.5,120.8,114.2,64.2,55.6,31.2,31.0,29.3 28.5,28.3,27.8,25.3.
HRMS(ESI)m/z calcd for C 23 H 27 N 4 O 7 S[M+H] + 503.1595,found 503.1580.
EXAMPLE 11 preparation of Compound 4k
Prepared as described in example 1 using 4- (3-fluoromethoxy) aniline instead of aniline, to give a pale yellow solid in 86.7% yield.
1 H NMR(600MHz,CDCl 3 ):δ8.40(d,J＝7.9Hz,1H),7.85(d,J＝13.9Hz,1H),7.52(d,J＝8.9Hz,2H),7.14(t,J＝7.7Hz,3H),4.12(t,J＝6.5Hz,2H),3.26(t,J＝7.3Hz,2H),2.75(t,J＝6.2Hz,2H),2.68(t,J＝6.2Hz,2H),1.85–1.80(m,2H),1.68–1.64(m,2H),1.57–1.52(m,2H),1.45–1.40(m,2H)； 13 C NMR(150MHz,CDCl 3 ):δ173.3,169.9,149.1,145.0,142.4,141.9,136.6,132.4,130.8,121.6,121.2(d,J＝255.0Hz),120.8,120.3,64.7,31.8,31.5,29.2,28.3,28.2,27.6,25.31.
HRMS(ESI)m/z calcd for C 23 H 24 F 3 N 4 O 7 S[M+H] + 557.1312,found 557.1311.
EXAMPLE 12 preparation of Compound 4l
Prepared as described in example 1 using 3, 4-dimethoxyaniline instead of aniline to give a yellow solid in 84.8% yield.
1 H NMR(600MHz,DMSO–d 6 ):δ9.80(s,1H),8.53(d,J＝7.9Hz,1H),7.44(d,J＝8.0Hz,1H),7.25(d,J＝2.3Hz,1H),7.03–7.01(m,1H),6.81(d,J＝8.7Hz,1H),4.04(t,J＝6.5Hz,2H),3.68(s,3H),3.67(s,3H),3.31(t,J＝6.9Hz,2H),2.57(s,4H),1.74–1.69(m,2H),1.60–1.56(m,2H),1.48–1.43(m,2H),1.39–1.34(m,2H)； 13 C NMR(150MHz,DMSO–d 6 ):δ172.9,169.8,149.6,148.9,145.0,143.1,140.5,133.4,132.7,132.5,122.5,112.4,111.1,104.5,64.2,56.1,55.7,31.3,31.0,29.2,28.5,28.3,27.8,25.3.
HRMS(ESI)m/z calcd for C 24 H 29 N 4 O 8 S[M+H] + 533.1701,found 533.1709.
Example 13 preparation of Compound 4m
Prepared as described in example 1, substituting 3-chloro-4-fluoroaniline for aniline, to give a yellow solid in 86.1% yield.
1 H NMR(600MHz,DMSO–d 6 ):δ10.19(s,1H),8.54(d,J＝8.0Hz,1H),7.87–7.86(m,1H),7.45(d,J＝8.0Hz,1H),7.39–7.37(m,1H),7.31(t,J＝9.1Hz,1H),4.03(t,J＝6.5Hz,2H),3.31(t,J＝7.4Hz,2H),2.59(s,4H),1.74–1.69(m,2H),1.60–1.55(m,2H),1.48–1.43(m,2H),1.38–1.33(m,2H)； 13 C NMR(150MHz,DMSO–d 6 ):δ172.8,170.6,154.1(d,J＝241.5Hz),149.6,143.1,140.6,136.9,132.8,132.5,122.5,120.6,119.5,117.4,117.3,64.3,31.3,31.0,29.1,28.5,28.3,27.8,25.3.
HRMS(ESI)m/z calcd for C 22 H 23 ClFN 4 O 6 S[M+H] + 525.1005,found 525.0851.
EXAMPLE 14 preparation of Compound 4n
Prepared as described in example 1, substituting 3-dimethylaminopropylamine for aniline, gave a yellow solid in 79.0% yield.
1 H NMR(600MHz,DMSO–d 6 ):δ8.57(d,J＝8.0Hz,1H),8.14(t,J＝5.6Hz,1H),7.53(d,J＝8.0Hz,1H),4.01(t,J＝6.6Hz,2H),3.37–3.35(m,4H),3.11(q,J＝6.4Hz,2H),2.99–2.97(m,2H),2.69(s,6H),2.36(t,J＝6.9Hz,2H),1.80–1.74(m,4H),1.60–1.55(m,2H),1.51–1.46(m,2H),1.39–1.34(m,2H)； 13 C NMR(150MHz,DMSO–d 6 ):δ172.9,171.5,149.7,143.2,140.5,132.9,132.6,122.7,64.2,54.8,42.5,36.1,31.1,31.3,29.4,28.5,28.3,27.8,25.3,24.7.
HRMS(ESI)m/z calcd for C 21 H 32 N 5 O 6 S[M+H] + 483.2096,found 483.2090.
EXAMPLE 15 preparation of Compound 4o
Prepared as described in example 1, substituting 3-diethylaminopropylamine for aniline, and gave a yellow oily liquid in 52.3% yield.
1 H NMR(600MHz,DMSO–d 6 ):δ8.56(d,J＝8.0Hz,1H),8.19(t,J＝5.6Hz,1H),7.52(d,J＝8.0Hz,1H),4.01(t,J＝6.6Hz,2H),3.37(t,J＝7.4Hz,2H),3.13(q,J＝6.3Hz,2H),3.07(q,J＝7.1Hz,4H),3.00(t,J＝8.1Hz,2H),2.37(t,J＝9.8Hz,2H),1.81–1.74(m,4H),1.60–1.55(m,2H),1.51–1.46(m,2H),1.40–1.35(m,2H),1.22(t,J＝7.3Hz,6H)； 13 C NMR(150MHz,DMSO–d 6 ):δ172.9,171.4,149.6,143.1,140.5,132.8,132.5,122.7,64.2,55.4,48.8,46.5,36.3,31.1,30.3,29.4,28.4,28.3,27.8,25.3,23.8,8.9.
HRMS(ESI)m/z calcd for C 22 H 34 N 5 O 6 S[M+H] + 510.2381,found 510.2379.
EXAMPLE 16 preparation of Compound 4p
Prepared as described in example 1, substituting 2-dimethylaminoethylamine for aniline, to give a brown solid in 73.2% yield.
1 H NMR(600MHz,DMSO–d 6 ):δ8.57(d,J＝7.9Hz,1H),8.32-8.31(m,1H),7.52(d,J＝7.9Hz,1H),4.01(t,J＝6.4Hz,2H),3.41–3.38(m,2H),3.37(t,J＝7.2Hz,2H),3.09(t,J＝5.9Hz,2H),2.73(s,6H),2.52–2.51(m,2H),2.41(t,J＝6.8Hz,2H),1.79–1.74(m,2H),1.60–1.55(m,2H),1.51–1.46(m,2H),1.39–1.34(m,2H)； 13 C NMR(150MHz,DMSO–d 6 ):δ172.9,171.8,149.6,143.1,140.5,132.8,132.5,122.7,64.2,56.2,42.7,34.3,31.0,30.4,29.3,28.4,28.3,27.8,25.3.
HRMS(ESI)m/z calcd for C 20 H 30 N 5 O 6 S[M+H] + 468.1911,found 468.1900.
EXAMPLE 17 preparation of Compound 4q
Prepared as described in example 1, substituting 4- (2-aminoethyl) morpholine for aniline, to give a brown solid in 73.2% yield.
1 H NMR(600MHz,DMSO–d 6 ):δ8.56(d,J＝8.0Hz,1H),7.79(t,J＝5.5Hz,1H),7.50(d,J＝8.0Hz,1H),4.00(t,J＝6.6Hz,2H),3.54(t,J＝4.5Hz,4H),3.37(t,J＝7.4Hz,2H),3.15(q,J＝6.7Hz,2H),2.48(t,J＝6.8Hz,2H),2.34–2.32(m,6H),2.30(t,J＝6.9Hz,2H),1.79–1.74(m,2H),1.60–1.55(m,2H),1.51–1.46(m,2H),1.40–1.35(m,2H)； 13 C NMR(150MHz,DMSO–d 6 ):δ172.9,171.0,149.6,143.1,140.5,132.8,132.6,122.6,66.6,64.1,57.9,53.8,36.4,31.0,30.3,29.5,28.4,28.3,27.8,25.3.
HRMS(ESI)m/z calcd for C 22 H 32 N 5 O 7 S[M+H] + 510.2017,found 510.2013.
EXAMPLE 18 preparation of Compound 4r
Prepared as described in example 1, substituting 1- (2-aminoethyl) pyrrolidine for aniline, gave a yellow oily body in 51.2% yield.
1 H NMR(600MHz,DMSO–d 6 ):δ8.57(d,J＝7.9Hz,1H),8.27(t,J＝5.5Hz,1H),7.52(d,J＝8.0Hz,1H),4.01(t,J＝6.6Hz,2H),3.40–3.34(m,8H),3.14(t,J＝5.8Hz,2H),2.52–2.51(m,2H),2.41(t,J＝6.9Hz,2H),1.91(s,4H),1.79–1.74(m,2H),1.60–1.55(m,2H),1.51–1.46(m,2H),1.40–1.35(m,2H)； 13 C NMR(150MHz,DMSO–d 6 ):δ172.9,171.8,149.7,143.1,140.5,132.8,132.6,122.7,64.2,53.6,53.5,35.6,31.0,30.4,29.3,28.4,28.3,27.8,25.3,23.1.
HRMS(ESI)m/z calcd for C 22 H 32 N 5 O 6 [M+H] + 494.2068,found 494.2073.
EXAMPLE 19 preparation of Compound 4s
Prepared as described in example 1, substituting morpholine for aniline, gave a pale yellow solid in 76.8% yield.
1 H NMR(600MHz,DMSO–d 6 ):δ8.56(d,J＝8.0Hz,1H),7.50(d,J＝8.0Hz,1H),4.01(t,J＝6.5Hz,2H),3.56(t,J＝4.7Hz,2H),3.51(t,J＝4.8Hz,2H),3.44(t,J＝4.6Hz,2H),3.40(t,J＝4.7Hz,2H),3.37(t,J＝7.4Hz,2H),2.57–2.55(m,2H),2.49–2.47(m,2H),1.79–1.74(m,2H),1.60–1.55(m,2H),1.51–1.46(m,2H),1.40–1.35(m,2H)； 13 C NMR(150MHz,DMSO–d 6 ):δ173.0,170.0,149.6,143.1,140.5,132.8,132.6,122.6,66.5,64.1,45.6,42.0,31.0,29.3,28.4,28.3,27.8,27.7,25.3.
HRMS(ESI)m/z calcd for C 20 H 27 N 4 O 7 S[M+H] + 467.1595,found 467.1593.
EXAMPLE 20 preparation of Compound 4t
Prepared as described in example 1, substituting piperidine for aniline, to give a yellow solid in 77.5% yield.
1 H NMR(600MHz,DMSO–d 6 ):δ8.54(d,J＝8.0Hz,1H),7.49(d,J＝8.0Hz,1H),4.00(t,J＝6.6Hz,2H),3.38(t,J＝5.5Hz,4H),3.35–3.33(m,2H),2.54–2.52(m,2H),2.47–2.45(m,2H),1.79–1.74(m,2H),1.60–1.54(m,4H),1.51–1.46(m,4H),1.40–1.35(m,4H)； 13 C NMR(150MHz,DMSO–d 6 ):δ173.0,169.3,149.6,143.1,140.5,132.8,132.5,122.6,64.1,46.1,42.5,31.0,29.4,28.5,28.3,27.8,27.7,26.4,25.8,25.3,24.5.
HRMS(ESI)m/z calcd for C 21 H 29 N 4 O 6 S[M+H] + 465.1802,found 465.1809.
(III) detection of GSTP1 and GSTM2 inhibition by Compounds
The experimental method comprises the following steps: the inhibition of GSTP1 and GSTM2 by compounds 4a-4t was detected by glutathione-S transferase kit.
The first part is an enzymatic reaction. 30 μ L of the substrate solution (prepared by mixing the working solution A and the GSH standard solution 1mmol/L at a ratio of 1). Compounds 4n,4o,4p and 4r to be tested were prepared as stock solutions with distilled water, and the remaining compounds were prepared as stock solutions with DMSO solutions and diluted to a range of concentrations with distilled water just before use, wherein the final concentration of DMSO was not more than 4 ‰ (the same experiment below). Compounds with different concentrations were mixed with 20nM GSTP1 protein and 5nM GSTM2 protein, respectively, and the total volume of 10. Mu.L of the mixture of protein and compound was added to the assay group, and then the mixture of protein and compound was added to the control group after being subjected to a water bath at 37 ℃ for 10 min.
The second part is a color reaction. 200 μ L of C working solution and 50 μ L of D working solution are added into the control group, the measurement group, the blank group and the standard group respectively for standby, 200 μ L of B working solution is added into the blank group, and 200 μ L of 20 μmol/L GSH standard solution is added into the standard group. Standing at room temperature for 15min, and detecting absorbance values of each group at 412nm with a microplate reader.
GST activity calculation formula:
the activity of GST under each concentration is calculated by the above formula, the inhibition rate is calculated, and a concentration-inhibition rate curve is made to calculate IC 50 The value is obtained. Compound 2 and nbdheex were positive controls. The inhibition of glutathione transferase GSTP1 and GSTM2 by the compounds at different concentrations was observed, and the results are shown in Table 2.
TABLE 2 inhibition of GSTP1 and GSTM2 by compounds
As can be seen from the data in Table 2, although Compound 2 and NBDHEX have good inhibitory effects on GSTP1, they have stronger inhibitory effects on GSTM 2. Compared with the parent compound NBDHEX, the introduction of the polyamino group in the invention ensures that the inhibition effect of partial compounds on GSTP1 is improved, and the inhibition effect on GSTM2 is obviously reduced, wherein most of the polyamino compounds containing aliphatic rings have better effect on GSTP1 inhibition than those of the polyamino compounds containing aromatic rings. Notably, all representative compounds have less inhibition of GSTM2 than NBDHEX. Of these, the two compounds 4n and 4s with the best activity, their IC for GSTP1 50 The values were 0.16. Mu.M and 0.33. Mu.M, respectively, but the inhibition of GSTM2 was 4.5 times and 8.5 times lower than NBDHEX, respectively. NBDHEX is 73-fold selective for GSTM2 protein compared to GSTP1, while compounds 4n and 4s are 1.8-fold and 1.9-fold selective for GSTM2 protein, respectively.
(IV) in vitro cytotoxic Activity assay of Compounds
The experimental method comprises the following steps: representative compounds of the invention were tested for cytotoxic activity using the MTT method. The cells in logarithmic growth phase are counted and inoculated into 96-well culture plates with about 8000-10000 cells per well. Culturing overnight, and administering after cell adherenceThe administration group and the control group were provided separately. The compounds 4n,4o,4p and 4r to be tested were prepared as stock solutions in sterile water, the remaining compounds were prepared as stock solutions in DMSO, and diluted to a range of concentrations with cell culture media just before use, with the final concentration of DMSO not exceeding 4% o (the same experiment below). Each concentration was provided with 3 multiple wells. After adding the drug, the mixture is cultured for 72h, 20 mu L of MTT with the concentration of 5mg/mL is added, the mixture is incubated for 4h at 37 ℃, the supernatant is discarded, and 150 mu L of DMSO is added for dissolution. Measuring the OD value of each hole by using an enzyme-labeling instrument at 490 nm wavelength, calculating the inhibition rate, and calculating the IC by using a concentration-inhibition rate curve 50 The value is obtained.
The in vitro antiproliferative activity of compounds 4a-4t on lung cancer cell a549, melanoma cell B16, osteosarcoma cell 143B, osteosarcoma cell HOS and human umbilical vein vascular endothelial cell HUVEC was tested, and compound 2 and nbdheex as positive controls. Observing the inhibition of the compound on the growth of tumor cells under different concentrations, and calculating the inhibition rate and IC thereof 50 The cytotoxic activity of the drug was evaluated and the results are shown in table 3.
TABLE 3 cytotoxic Activity of Compounds
As can be seen from the data in table 3, although compound 2 and NBDHEX have good cytotoxic effects on tumor cells, they are also highly toxic to normal cells. The compounds 4a-4t have stronger antitumor activity on four cancer cells A549, B16, 143B and HOS, but the cytotoxicity on normal cells is lower than that of the compounds 2 and NBDHEX. IC of two compounds 4n and 4s with the best antitumor Activity 50 The values are between 0.82 and 1.85. Mu.M, and their toxicity to normal cells is 3.2 times lower than that of NBDHEX and 10.7 times lower than that of NBDHEX. The data in Table 3 show that the introduction of polyamino groups can improve the antitumor activity of partial compounds compared with NBDHEX and obviously reduce the toxicity to normal cells, wherein the polyamino groups contain fat ringsThe ammonia compound has a better antitumor activity than the polyamino compound containing an aromatic ring.
Claims (10)
1. An antitumor compound taking GSTP1 as a target spot and pharmaceutically acceptable salts thereof are characterized by comprising a compound with a structure shown as a formula I:
wherein n =1-3;
when R is 1 When is H, R 2 Is aryl or alkyl; when R is 2 When aryl, is selected from phenyl, mono-or di-substituted phenyl, and the substituent is CH 3 、OCH 3 、OCF 3 F, cl or Br, and the substituent is at any position of ortho, meta or para; when R is 2 When it is an alkyl group, it is selected from C 1～4 Dimethylamino radical of straight-chain alkyl, C 1～4 Diethylamino of straight-chain alkyl, C 1～4 Morpholinyl of straight-chain alkyl, C 1～4 Piperidinyl or C of straight-chain alkyl groups 1～4 Pyrrolidinyl of straight chain alkyl;
or, R 1 And R 2 Morpholine or piperidyl which forms a cyclic structure with the N atom.
2. The GSTP 1-targeted anti-tumor compound and pharmaceutically acceptable salts thereof according to claim 1, wherein the compound is selected from the group consisting of the following compounds 4a-4t:
3. a method for preparing the GSTP 1-targeted antitumor compound of claim 1 and pharmaceutically acceptable salts thereof, comprising the steps of:
TBTU stands for the condensing agent tetrafluoroboric acid-2- (1H-benzotriazol-1-yl) -1, 3-tetramethyluronium, et 3 N represents triethylamine, and DMF represents solvent N, N-dimethylformamide.
4. The method for preparing the antitumor compound targeting GSTP1 and the pharmaceutically acceptable salt thereof according to claim 3, which comprises the following steps:
dissolving compound 3 and TBTU in anhydrous DMF, stirring at room temperature, adding Et 3 And N, adding different substituted secondary amines, stirring the reaction solution at 30-40 ℃ for 1-3h, then removing the solvent under reduced pressure, and separating the concentrated solution by silica gel column chromatography, wherein the eluent is a mixed solvent of dichloromethane and methanol to obtain a yellow or brown solid product or an oily substance.
5. The process for preparing GSTP 1-targeted antitumor compounds and pharmaceutically acceptable salts thereof according to claim 3, wherein the compound 3 is prepared according to the following reaction formula:
wherein n =1-3; DMAP for 4-dimethylaminopyridine and DCM for CH 2 Cl 2 。
6. The method for preparing the GSTP 1-targeted antitumor compound and the pharmaceutically acceptable salt thereof according to claim 5, comprising the following steps:
synthesis of Compound 3: dissolving 2 in CH 2 Cl 2 Adding naphthenic dianhydride and DMAP, reacting overnight at 40-50 ℃, cooling to room temperature, concentrating the reaction solution, and performing column chromatography separation to obtain a yellow product 3, wherein the eluent is a mixed solvent of dichloromethane and methanol.
7. A pharmaceutical composition comprising a compound according to any one of claims 1 to 2 and pharmaceutically acceptable salts thereof.
8. The use of the GSTP 1-targeted anti-tumor compound of claim 1 and pharmaceutically acceptable salts thereof for the preparation of a GSTP1 inhibitor.
9. The use of the GSTP 1-targeted anti-tumor compound of claim 1 and pharmaceutically acceptable salts thereof in the preparation of GSTM2 inhibitors.
10. The use of the GSTP 1-targeted anti-tumor compound of claim 1 and pharmaceutically acceptable salts thereof for the preparation of a medicament for treating lung cancer, melanoma, osteosarcoma.
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