CN113788810B - Chromone nitrogen mustard derivative and anti-tumor application - Google Patents
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Abstract
The invention discloses a class of chromone nitrogensMustard derivative and anti-tumor application, belonging to the fields of natural medicine and medicinal chemistry. In particular to a preparation method of a series of chromone nitrogen mustard derivatives with anti-tumor activity and new application in anti-tumor drugs. The chromone nitrogen mustard derivative and the pharmaceutically acceptable salt thereof are shown as a general formula I. Wherein R and X are as described in the claims and the description.
Description
Technical Field
The invention belongs to the field of natural medicines and medicinal chemistry, relates to a chromone nitrogen mustard derivative and anti-tumor application, and particularly relates to a preparation method of a series of chromone nitrogen mustard derivatives with anti-tumor activity and application of the chromone nitrogen mustard derivatives in the aspect of anti-tumor.
Background
The chromone backbone is an important component of a large number of biologically active molecules, and is also a core moiety of many natural products, lead compounds, and clinical drugs. The chromone can be synthesized into derivatives with various structures, and can be used as a lead compound for structural modification to synthesize various derivatives with different pharmacological activities. At present, chromone and derivatives thereof become one of the most important synthetic compounds with anticancer activity, and the synthesis and structure modification of chromone are actively researched at home and abroad.
Nitrogen mustards are a class of DNA alkylating agents and have now been developed as a variety of chemotherapeutic agents with a broad spectrum of anti-tumor activity. However, because of its non-specificity to cancer cells, it is often necessary to use large doses to achieve the effect of killing cancer cells. The use of high doses of nitrogen mustard causes serious side effects and drug resistance, limiting its further clinical application. Therefore, many researchers have structurally modified nitrogen mustards in order to obtain more active, less toxic and more selective antitumor candidate compounds.
Disclosure of Invention
The invention aims to solve the technical problem of searching the chromone nitrogen mustard derivative with good anti-tumor activity and the pharmaceutically acceptable salt thereof and further providing a pharmaceutical composition.
In order to solve the technical problems, the invention provides the following technical scheme:
a chromone mustard derivative and pharmaceutically acceptable salts thereof have the following structural general formula I:
wherein R is an alkyl group having 1 to 8 carbon atoms or an alkoxy group having 1 to 8 carbon atoms; the heteroatom X is N, O, S or Se.
Preferably, R is an alkyl group having 1 to 6 carbon atoms or an alkoxy group having 1 to 6 carbon atoms; the heteroatom X is N, O or S.
More preferably, R is an alkyl group containing 1 to 4 carbon atoms or an alkoxy group containing 1 to 4 carbon atoms; the heteroatom X is N or O.
Further, the following derivatives and pharmaceutically acceptable salts thereof are preferably selected from the following structural formulas a to d:
the derivative of the invention can be prepared by the following method:
(1) TransformingReacting the compound 1a-b with phosphorus oxychloride in N, N-dimethylformamide at room temperature to obtain an intermediate 2a-b; then the intermediate 2a-b is dissolved in isopropanol and alkaline Al is added 2 O 3 Carrying out reflux reaction to obtain a compound 3a-b; dissolving the compounds 3a-b in dichloromethane, dropwise adding phosphorus tribromide under an ice bath condition, transferring to room temperature for reaction, dissolving the treated solid in N, N-dimethylformamide, adding ammonia water, and reacting at room temperature to obtain compounds 4a-b;
(2) Reacting the compound 5 with ethylene oxide in an acetic acid aqueous solution to obtain an intermediate 6; the intermediate 6 is firstly reacted with phosphorus oxychloride, and then the compound 7 is obtained under the condition of 10% hydrochloric acid aqueous solution.
(3) Dissolving the compound 3a-b or 4a-b in anhydrous dichloromethane, sequentially adding EDCI, DMAP or HOBt, and reacting with the compound 7 at room temperature to obtain a target compound 8a-d.
A pharmaceutical composition, which comprises a therapeutically effective amount of the chromone nitrogen mustard derivative shown in the general formula I and pharmaceutically acceptable salts thereof and a pharmaceutically acceptable carrier.
The use of the chromone nitrogen mustard derivative shown in the general formula I and the pharmaceutically acceptable salt thereof in preparing medicaments for treating tumor diseases.
Furthermore, the tumor is breast cancer tumor or liver cancer tumor.
The application of the pharmaceutical composition in preparing medicines for treating tumor diseases.
Furthermore, the tumor is breast cancer tumor or liver cancer tumor.
The invention takes chromone as a lead compound, designs and synthesizes a series of chromone nitrogen mustard derivatives, and tests the biological activity of the synthesized derivatives in the aspect of anti-tumor.
Pharmacological tests prove that the chromone nitrogen mustard derivative has good anti-tumor cell proliferation effect and can be used for further preparing anti-tumor drugs.
Detailed Description
The following non-limiting examples will allow one of ordinary skill in the art to more fully understand the present invention, but are not intended to limit the invention in any way.
The synthesis route of the derivatives of the embodiment of the invention is as follows:
example 1
(1) 500mg of compound 1a (3.33 mmol) was dissolved in 10mL of DMF, and 630. Mu.L of phosphorus oxychloride (6.72 mmol) was added dropwise and reacted at room temperature for 12 hours. TLC monitoring, reaction is almost complete, 15mL water is added, crystal precipitation is carried out, suction filtration and drying are carried out, and intermediate 2a 402.4mg is obtained. 50mg of intermediate 2a (0.27 mmol) are dissolved in 10mL of isopropanol and 1g of basic Al are added 2 O 3 (9.80 mmol) and then the reaction was refluxed at 75 ℃ for 5h. TLC monitoring, reaction completion, suction filtration, filtrate concentration to get crude product, silica gel column chromatography (DCM: meOH) separation to get compound 3a (R = -CH) 3 )。
(2) 5mL of ethylene oxide (0.10 mol) was added to a suspension of 1.53g of ethyl 4-aminobenzoate 5 (9.26 mmol) dissolved in 12mL of a 65% aqueous acetic acid solution, and stirred at room temperature for 24 hours. After completion of the reaction, the reaction mixture was extracted 3 times with ethyl acetate, washed 1 time with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to give intermediate 6.64g. Slowly dropwise adding 2mL of POCl under ice bath condition 3 In 1.5g of intermediate 6 (6.00 mmol), the reaction was carried out in an oil bath at 50 ℃ for 0.5h. Then adding 3mL of 10% hydrochloric acid aqueous solution to react for 12h at room temperature, filtering, washing filter residue, and concentrating in vacuum to obtain a compound 7.
(3) 50mg of compound 3a (0.26 mmol) was dissolved in 5mL of anhydrous dichloromethane, and 151.6mg of EDCI (0.80 mmol), 16.1mg of DMAP (0.13 mmol), 68.9mg of compound 7 (0.21 mmol) were added and reacted at room temperature for 12h. After the reaction was completed, the reaction solution was poured into water, extracted with dichloromethane 3 times, washed with saturated brine 1 time, and anhydrous Na 2 SO 4 Drying and concentrating to obtain a crude product. Separating with silica gel column chromatography (DCM: meOH)To the target compound 8a. White oil, 66.5% yield. 1 H NMR(CDCl 3 ,400MHz),δ:8.12(1H,s,2-H),8.02(1H,d,J＝2.0Hz,5-H),7.94(2H,d,J＝9.1Hz,Ar-H),7.47(1H,dd,J＝8.6,2.0Hz,7-H),7.34(1H,d,J＝8.6Hz,8-H),6.63(2H,d,J＝9.1Hz,Ar-H),5.27(2H,s,-CH 2 ),3.78(4H,t,J＝7.0Hz,-CH 2 ),3.64(4H,t,J＝7.0Hz,-CH 2 ),2.45(3H,s,-CH 3 )； 13 C NMR(CDCl 3 ,100MHz),δ:176.76,166.40,155.42,154.75,149.83,135.36,135.07,131.98(2),125.20,123.75,119.77,118.59,117.95,110.86(2),58.12,53.27(2),40.20(2),20.95；HRMS(ESI)m/z calcd for C 22 H 20 Cl 2 NO 4 [M-H] - 432.0769,found 432.0748。
Example 2
Example 1 the procedure for the synthesis of 3a in step (1) was replaced by: 553mg of Compound 1b (3.33 mmol) were dissolved in 10mL of DMF, and 630. Mu.L of phosphorus oxychloride (6.72 mmol) were added dropwise and reacted at room temperature for 12 hours. TLC monitoring, reaction is almost complete, 15mL water is added, crystallization is carried out, suction filtration and drying are carried out, and the intermediate 2b 410mg is obtained. 55mg of intermediate 2b (0.27 mmol) were dissolved in 10mL of isopropanol and 1g of basic Al was added 2 O 3 (9.80 mmol) and then the reaction was refluxed at 75 ℃ for 5h. TLC monitoring, reaction completed, suction filtration, filtrate concentration to get crude product, silica gel column chromatography (DCM: meOH) separation to get compound 3b (R = -OCH) 3 )。
The remaining steps were performed according to the synthetic method of example 1 to obtain compound 8b as a yellow oil in 43.8% yield. 1 H NMR(CDCl 3 ,400MHz),δ:8.14(1H,s,2-H),7.95(2H,d,J＝9.1Hz,Ar-H),7.61(1H,d,J＝3.1Hz,5-H),7.40(1H,d,J＝9.1Hz,8-H),7.26(1H,dd,J＝9.1,3.1Hz,7-H),6.64(2H,d,J＝9.1Hz,Ar-H),5.27(2H,s,-CH 2 ),3.90(3H,s,-OCH 3 ),3.79(4H,t,J＝6.8Hz,-CH 2 ),3.64(4H,t,J＝6.8Hz,-CH 2 )； 13 C NMR(CDCl 3 ,100MHz),δ:176.56,166.41,157.08,155.32,151.34,149.83,132.00(2),124.70,123.95,119.62,119.18,118.62,110.86(2),104.95,58.13,55.95,53.29(2),40.10(2)；HRMS(ESI)m/z calcd for C 22 H 20 Cl 2 NO 5 [M-H] - 448.0719,found 448.0714。
Example 3
Example 1 the procedure for the synthesis of 3a in step (1) was replaced by: 500mg of compound 1a (3.33 mmol) was dissolved in 10mL of DMF, and 630. Mu.L of phosphorus oxychloride (6.72 mmol) was added dropwise and reacted at room temperature for 12 hours. TLC monitoring, reaction is almost complete, 15mL water is added, crystal precipitation is carried out, suction filtration and drying are carried out, and intermediate 2a 402.4mg is obtained. 50mg of intermediate 2a (0.27 mmol) are dissolved in 10mL of isopropanol and 1g of basic Al are added 2 O 3 (9.80 mmol) and then the reaction was refluxed at 75 ℃ for 5h. TLC monitoring, reaction completion, suction filtration, filtrate concentration to get crude product, silica gel column chromatography (DCM: meOH) separation to get compound 3a 15mg. 500mg of Compound 3a (2.62 mmol) was dissolved in 10mL of DCM, 750. Mu.L of phosphorus tribromide (7.90 mmol) was added dropwise in an ice bath, reacted for 10min, and transferred to room temperature for reaction for 15h. TLC monitoring, complete reaction, dichloromethane extraction for 3 times, saturated salt water washing for 1 time, anhydrous Na 2 SO 4 Dried, filtered and concentrated to give 652mg of a yellow solid. The resulting solid was dissolved in 10mL of DMF, and 10mL of aqueous ammonia was added to the solution to react at room temperature overnight. TLC monitoring, complete reaction, ethyl acetate extraction 3 times, saturated salt water washing 1 time, anhydrous Na 2 SO 4 Drying, filtering and concentrating to obtain a crude product. Separating by silica gel column chromatography (DCM: meOH) to obtain compound 4a (R = -CH) 3 )。
Example 1 the procedure for the synthesis of 8a in step (3) was replaced by: 26.4mg of compound 4a (0.14 mmol) was dissolved in 4mL of anhydrous dichloromethane, and 39.9mg of EDCI (0.21 mmol), 22.5mg of HOBt (0.17 mmol), 36.4mg of compound 7 (0.14 mmol) were added and reacted at room temperature for 6h. After the reaction was completed, the reaction solution was poured into water, extracted with dichloromethane 3 times, washed with saturated brine 1 time, and anhydrous Na 2 SO 4 Drying and concentrating to obtain a crude product.Silica gel column chromatography (DCM: meOH) afforded the title compound 8c.
The remaining steps were performed according to example 1 to obtain compound 8c as a white solid with a yield of 36.8%. 1 H NMR(CDCl 3 ,400MHz),δ:8.17(1H,s,2-H),7.98(1H,d,J＝2.0Hz,5-H),7.70(2H,d,J＝8.9Hz,Ar-H),7.48(1H,dd,J＝8.6,2.0Hz,7-H),7.36(1H,d,J＝8.6Hz,8-H),7.14(1H,s,-NH),6.64(2H,d,J＝8.9Hz,Ar-H),4.45(2H,d,J＝5.6Hz,-CH 2 ),3.76(4H,m,-CH 2 ),3.62(4H,m,-CH 2 ),2.45(3H,s,-CH 3 )； 13 C NMR(CDCl 3 ,100MHz),δ:178.5,167.0,154.9,154.5,148.7,135.3,135.2,129.1(2),124.8(2),123.6,121.0,118.1,111.1(2),53.3(2),40.2(2),36.3,20.9；HRMS(ESI)m/z calcd for C 22 H 21 Cl 2 N 2 O 3 [M-H] - 431.0929,found 431.0921。
Example 4
Example 1 the procedure for the synthesis of 3a in step (1) was replaced by: 553mg of Compound 1b (3.33 mmol) were dissolved in 10mL of DMF, and then 630. Mu.L of phosphorus oxychloride (6.72 mmol) was added dropwise and reacted at room temperature for 12 hours. TLC monitoring, reaction is almost complete, 15mL water is added, crystallization is separated out, suction filtration and drying are carried out, and intermediate 2b 410mg is obtained. 55mg of intermediate 2b (0.27 mmol) were dissolved in 10mL of isopropanol and 1g of basic Al was added 2 O 3 (9.80 mmol) and then the reaction was refluxed at 75 ℃ for 5h. TLC monitoring, reaction completion, suction filtration, filtrate concentration to get crude product, silica gel column chromatography (DCM: meOH) separation to get compound 3b 22mg. 540mg of compound 3b (2.62 mmol) was dissolved in 10mL of DCM, 750. Mu.L of phosphorus tribromide (7.90 mmol) was added dropwise in an ice bath, reacted for 10min, and transferred to room temperature for reaction for 15h. TLC monitoring, reaction completion, dichloromethane extraction 3 times, saturated salt water washing 1 time, anhydrous Na 2 SO 4 Dried, filtered and concentrated to afford 681mg of a yellow solid. The resulting solid was dissolved in 10mL of DMF, and 10mL of aqueous ammonia was added to the solution to react at room temperature overnight. TLC monitoring, complete reaction, ethyl acetate extraction 3 times, saturated foodWashing with saline water for 1 time, and removing anhydrous Na 2 SO 4 Drying, filtering and concentrating to obtain a crude product. Separating by silica gel column chromatography (DCM: meOH) to obtain compound 4b (R = -OCH) 3 )。
Example 1 the procedure for the synthesis of 8a in step (3) was replaced by: 28.7mg of compound 4b (0.14 mmol) were dissolved in 4mL of anhydrous dichloromethane, and 39.9mg of EDCI (0.21 mmol), 22.5mg of HOBt (0.17 mmol), 36.4mg of compound 7 (0.14 mmol) were added and reacted at room temperature for 6h. After the reaction was completed, the reaction solution was poured into water, extracted with dichloromethane 3 times, washed with saturated brine 1 time, and washed with anhydrous Na 2 SO 4 Drying and concentrating to obtain a crude product. Silica gel column chromatography (DCM: meOH) afforded title compound 8d.
The remaining steps were performed according to example 1 to obtain compound 8d as a white solid with a yield of 43.5%. 1 H NMR(CDCl 3 ,400MHz),δ:8.17(1H,s,2-H),7.70(2H,d,J＝8.8Hz,Ar-H),7.55(1H,d,J＝3.1Hz,5-H),7.40(1H,d,J＝9.1Hz,8-H),7.27(1H,dd,J＝9.1,3.1Hz,7-H),7.11(1H,s,-NH),6.64(2H,d,J＝8.8Hz,Ar-H),4.46(2H,d,J＝5.7Hz,-CH 2 ),3.89(3H,d,-OCH 3 ),3.76(4H,m,-CH 2 ),3.62(4H,m,-CH 2 )； 13 C NMR(CDCl 3 ,100MHz),δ:178.3,167.0,157.0,154.4,151.6,148.7,129.1(2),124.6,124.1,120.4,119.8,111.1(2),104.5,55.9,53.3(2),40.1(2),36.3,29.7；HRMS(ESI)m/z calcd for C 22 H 21 Cl 2 N 2 O 4 [M-H] - 447.0878,found 447.0878。
Example 5
The following are the results of pharmacological experiments with some of the compounds of the invention:
experimental equipment and reagent
Instrument clean bench (Su Jing group an Tai company)
Constant temperature incubator (Thermo electronic Corporation)
Enzyme-linked immunosorbent assay (BIO-RAD company)
Inverted biological microscope (Chongqing optical instrument factory)
Reagent cell culture medium RPMI-1640, DMEM (high-sugar) (GIBCO Co., ltd.) fetal bovine serum (Hangzhou Sijiqing Co., ltd.)
CCK-8 (Biosharp company product)
DMSO (Sigma Co.)
Cell lines of human breast cancer cell MCF-7, human breast cancer cell MDA-MB-231, human liver cancer cell HepG2 and Bel-7402
Experimental methods
Cell inhibitory activity test method
Cells at 37 deg.C, 5% 2 Culturing in an incubator with saturated humidity. The culture medium is high-glucose DMEM cell culture medium containing 10% heat-inactivated fetal calf serum, penicillin 100U/mL and streptomycin 100U/mL. The culture medium was changed for 48h, and after the cells were attached to the wall, they were digested with 0.25% trypsin for passage. The cells for experiment are all in logarithmic growth phase, and the CCK-8 method shows the cell activity>95％。
Taking a bottle of cells in logarithmic growth phase, adding digestive juice (0.125% trypsin +0.01% EDTA) for digestion, and counting 2-4 × 10 4 cell/mL, preparing cell suspension, inoculating on 96-well plate, 100 μ L/well, and placing in constant temperature CO 2 The culture was carried out in an incubator for 24 hours. The solution was changed, the test drug was added at 100. Mu.L/well, and cultured for 72 hours. CCK-8 was added to 96-well plates at 50. Mu.L/well and incubated in an incubator for 4 hours. The supernatant was aspirated, DMSO was added at 200. Mu.L/well and shaken on a shaker for 10 min. The test substances were examined at 6 concentrations of 0.001 to 100. Mu.M in ten-fold increments, and the cell inhibition rate at each concentration was calculated by measuring the absorbance of each well at a wavelength of 450nm using an enzyme-linked immunosorbent assay.
The inhibition rate calculation method comprises the following steps:
relative OD of drug sensitive wells = absolute OD of drug sensitive wells-absolute OD of blank control wells
Results of the experiment
TABLE 1 examples IC for antiproliferative activity against 2 human breast cancer and 1 human hepatoma cell lines 50 Value (μ M)
Pharmacological tests prove that the target derivative has better anti-breast cancer and anti-liver cancer cell proliferation activity, and can be used for further preparing anti-tumor drugs.
Claims (8)
1. A chromone mustard derivative of the general formula I:
wherein R is an alkyl group having 1 to 8 carbon atoms or an alkoxy group having 1 to 8 carbon atoms; the heteroatom X is N, O or S.
2. The chromone mustard derivative of formula I and its pharmaceutically acceptable salts of claim 1, wherein:
in the general formula I, R is alkyl containing 1-6 carbon atoms or alkoxy containing 1-6 carbon atoms.
3. The chromone mustard derivative of formula I and its pharmaceutically acceptable salts of claim 1, wherein:
in the general formula I, R is alkyl containing 1-4 carbon atoms or alkoxy containing 1-4 carbon atoms; the heteroatom X is N or O.
4. The chromone mustard derivative of formula I, or a pharmaceutically acceptable salt thereof, according to any one of claims 1-3, wherein: the structural formulas of the chromone nitrogen mustard derivative and the pharmaceutically acceptable salt thereof are shown as a-d:
5. a pharmaceutical composition characterized by: the pharmaceutical composition comprises a therapeutically effective amount of the chromone mustard derivative of formula I of any one of claims 1-4, and pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable carrier.
6. Use of the chromone mustard derivative of the general formula I and its pharmaceutically acceptable salts in any of claims 1-4 for the preparation of a medicament for the treatment of a neoplastic disease.
7. Use of the pharmaceutical composition of claim 5 for the preparation of a medicament for the treatment of a neoplastic disease.
8. Use according to claim 6 or 7, characterized in that: the tumor is breast cancer tumor or liver cancer tumor.
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