CN114940692B - Compound with anti-lung cancer effect and preparation method and application thereof - Google Patents

Compound with anti-lung cancer effect and preparation method and application thereof Download PDF

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CN114940692B
CN114940692B CN202210688316.9A CN202210688316A CN114940692B CN 114940692 B CN114940692 B CN 114940692B CN 202210688316 A CN202210688316 A CN 202210688316A CN 114940692 B CN114940692 B CN 114940692B
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CN114940692A (en
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方波
胡春生
赫佳馨
秦媛媛
谭娜
周新贵
胡馨丹
孟江平
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Chongqing University of Arts and Sciences
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Abstract

The invention discloses a compound with an anti-lung cancer effect, a preparation method and application thereof, wherein the compound introduces ligands containing multiple bonds (double bonds or triple bonds) into cisplatin to form a prodrug, improves the drug absorption of cisplatin, simultaneously plays the synergistic effect of cisplatin and the multiple bond ligands, enhances the effect of the drug on treating lung cancer, and the inhibition capability of part of the compound on cisplatin resistant A549 cells is obviously higher than that of the drug cisplatin.

Description

Compound with anti-lung cancer effect and preparation method and application thereof
Technical Field
The invention belongs to the technical field of medicinal chemistry, and particularly relates to a compound with an anti-lung cancer effect, and a preparation method and application thereof.
Background
Lung cancer is the second most advanced cancer with global onset, has a great threat to human health, and platinum drugs are very important anti-lung cancer drugs. Platinum drugs are known to exhibit completely different mechanisms and kinetics from conventional organic drugs, i.e., cisplatin can form crosslinks with DNA in the nucleus or cause internal crosslinking of DNA during cell division to inhibit cell division, thereby achieving the purpose of anti-tumor. Therefore, cisplatin was approved by the FDA in 1978 for clinical treatment of various cancers, and the drug has excellent efficacy on lung cancer, bladder cancer, testicular cancer, early ovarian cancer, head and neck cancer and breast cancer. However, with the wide application of platinum drugs, the drug resistance and systemic toxic and side effects of the drugs are not negligible. Moreover, the existing platinum drugs cannot well distinguish cancer cells from normal cells, resulting in low bioavailability and inducing a series of systemic toxicities. Therefore, the development of new platinum drugs is a hotspot in research today.
In recent years, tetravalent platinum [ Pt (IV) ] prodrugs, which are formed by introducing axial ligands based on divalent platinum [ Pt (II) ] drugs, have been receiving attention for their excellent antitumor efficacy, and tetravalent platinum prodrugs generally show better antitumor potential than the corresponding divalent platinum drugs. In addition, irreversible inhibitors against EGFR and BTK have had unprecedented success in the last two decades, and the core of these inhibitors is that the unsaturated bonds (double and triple bonds) in the structure can react with cysteines of the target protein to form irreversible covalent adducts.
Disclosure of Invention
Aiming at the prior art, the invention provides a compound with an anti-lung cancer effect, and a preparation method and application thereof, so as to solve the problems of drug resistance, systemic toxic and side effects and the like of the existing platinum drugs.
In order to achieve the above purpose, the technical scheme adopted by the invention is as follows: a compound with lung cancer resisting effect has the structural formula of
Wherein R is 1 And R is 2 Are electron withdrawing groups.
On the basis of the technical scheme, the invention can be improved as follows.
Further, R 1 And R is 2 Are respectively independent of
Further, R 1 And R is 2 The same applies.
The invention also provides a preparation method of the compound with the lung cancer resistance, which comprises the following steps:
(1) Dissolving a compound shown in a formula I in an organic solvent, adding alkali, stirring at room temperature for reaction for 0.4-0.6 h, dropwise adding 1-bromo-2-butyne or 3-bromopropene, stirring at room temperature overnight, and sequentially extracting, washing, drying and purifying to obtain a compound shown in a formula II;
wherein R is 3 Is that
(2) Dissolving a compound shown in a formula II in an organic solvent, adding trifluoroacetic acid, stirring at room temperature for reaction for 3-5 h, and then sequentially concentrating, alkalizing, separating liquid, washing and purifying to obtain the compound shown in a formula III;
(3) Dissolving a compound shown in a formula III in an organic solvent, adding cyclopentanedioic anhydride, stirring overnight at room temperature, and sequentially concentrating, filtering, washing and drying to obtain a compound shown in a formula IV;
(4) Dissolving a compound shown in a formula IV in an organic solvent, adding 2- (7-aza-benzotriazol) -N, N, N ', N' -tetramethyl urea hexafluorophosphate and triethylamine, stirring at room temperature for reaction for 0.4-0.6 h, adding dihydroxydichloro diammine platinum, stirring at room temperature for reaction for two days in dark, concentrating, and purifying to obtain the compound.
Further, in the step (1), the molar ratio of the compound shown in the formula I, the alkali, the 1-bromo-2-butyne or the 3-bromopropene is 9-11: 12-14: 11 to 13; in the step (1), the purification is column chromatography, and the volume ratio of the used reagents is 1: 6-20 of ethyl acetate and n-hexane.
Further, the ratio of the compound shown in the formula II to the trifluoroacetic acid in the step (2) is 8mmol: 3-5 mL; in the step (2), the purification is column chromatography, and the volume ratio of the used reagents is 1:4 to 9 of ethyl acetate and n-hexane.
Further, in the step (3), the molar ratio of the compound shown as the formula III to the cyclopentanedioanhydride is 2-4: 3.
further, in the step (4), the molar ratio of the compound shown in the formula IV, 2- (7-aza-benzotriazol) -N, N, N ', N' -tetramethyl urea hexafluorophosphate, triethylamine and dihydroxydichloro diammine platinum is 0.7-0.8: 0.7 to 0.8:0.7 to 0.8:0.2 to 0.4; in the step (4), the purification is column chromatography, and the volume ratio of the used reagents is 1:9 to 99 of methanol and methylene dichloride.
Further, the dihydroxydiammine platinum dichloride is prepared by the following steps: the dihydroxydichloro diammine platinum is prepared by the following steps: dropwise adding H into cisplatin water solution at room temperature 2 O 2 Stirring at 50-70 deg.c for 3-5 hr, filtering, re-crystallizing at 0-4 deg.c, filtering, washing and drying.
The invention also provides application of the compound with the lung cancer resistance in preparing a lung cancer resistance medicament.
The beneficial effects of the invention are as follows:
1. the ligand containing multiple bonds (double bonds or triple bonds) is introduced into cisplatin to form a prodrug, so that the drug absorption of cisplatin is improved, the synergistic effect of cisplatin and the multiple bond ligand is exerted, the effect of the drug for treating lung cancer is enhanced, and the inhibition capability of part of compounds on cisplatin resistant A549 cells is obviously higher than that of the drug cisplatin.
2. Cisplatin resistance is caused by close correlation with detoxification of cysteine-containing glutathione, and multiple bond ligands are introduced to serve as axial ligands of Pt (IV) prodrugs, so that the effect of the drugs on target proteins is enhanced, absorption is increased, side effects are reduced, and the treatment effect of platinum drugs on solid tumors, especially lung cancer, is enhanced.
Drawings
FIG. 1 is a graph showing the results of compounds 16, 28 inhibiting the formation of lung cancer cell clones;
FIG. 2 is a graph of the results of compounds 16, 28 promoting apoptosis;
FIG. 3 is a graph of the results of compounds 16, 28 promoting expression of apoptotic proteins;
FIGS. 4 and 5 are graphs showing the results of inhibiting the growth of lung cancer A549 cell subcutaneous tumor by the compounds 16 and 28
FIG. 6 is a synthetic flow chart of the present invention;
FIGS. 7 and 8 are hydrogen spectra and carbon spectra of compound 15 prepared according to the present invention;
FIGS. 9 and 10 are hydrogen and carbon spectra of compound 16 prepared according to the present invention;
FIGS. 11 and 12 are hydrogen spectra and carbon spectra of compound 17 prepared according to the present invention;
FIGS. 13 and 14 are hydrogen and carbon spectra of compound 27 prepared according to the present invention;
FIGS. 15 and 16 are hydrogen and carbon spectra of compound 28 prepared according to the present invention;
fig. 17 and 18 show the hydrogen spectrum and the carbon spectrum of the compound 29 prepared according to the present invention.
Detailed Description
The following describes the present invention in detail with reference to examples.
Example 1
A method for preparing a compound with an anti-lung cancer effect, which comprises the following steps:
(1) To a solution of 10.0mmol of 2- (BOC-aminomethyl) phenol in anhydrous N, N-dimethylformamide (15 mL) at room temperature was added 13.0mmol of Cs 2 CO 3 And stirred for 0.5h, then 12.0mmol of 1-bromo-2-butyne was added dropwise and stirred at room temperature overnight, the reaction was monitored by LC-MS, followed by quenching with 30mL of water, extraction 2 times with 30mL of ethyl acetate, combining the organic phases and washing 2 times with 40mL of water, 1 time with 40mL of brine, drying over 6g of anhydrous sodium sulfate, and purification by column chromatography (ethyl acetate/n-hexane (volume ratio: 1:12,1.2 l)) to give compound 6 (compound 6 in fig. 6) as a white solid;
compound 6 (tert-butyl 2- (but-2-yn-1-yloxy) phenyl) carbonate, 91.6%; MS (ESI, m/z): 262[ M+H ]] + .
(2) 8.0mmol of Compound 6 was dissolved in 12mL of dried dichloromethane at room temperature, 4mL of trifluoroacetic acid was added thereto and reacted at room temperature with stirring for 4 hours, the reaction was monitored by LC-MS, the resultant mixture was concentrated and methylene chloride and trifluoroacetic acid were removed, diluted with 30mL of water and 40mL of methylene chloride, the pH of the mixture was adjusted to 8.5 with 1mol/L of sodium hydroxide solution, followed by liquid separation, the resultant organic phase was washed with 30mL of water and 30mL of brine, and then purified by column chromatography (ethyl acetate/n-hexane (volume ratio: 1:6, 1.2L)) to give a pale brown oily product (Compound 9 in FIG. 6);
compound 9 (2- (but-2-yn-1-yloxy) aniline), 78.4%; MS (ESI, m/z): 162[ M+H ]] + .
(3) 3.0mmol of the pale brown oily product was dissolved in 15mL of dried dichloromethane at room temperature, 3.0mmol of cyclopentanedioic anhydride was added thereto and stirred at room temperature overnight, the reaction was monitored by LC-MS, the resultant mixture was concentrated and dichloromethane was removed, dichloromethane (5 mL) and n-hexane (15 mL) were then added to form a suspension, followed by filtration, and the cake was washed 2 times with 2mL of n-hexane, followed by vacuum drying to obtain a white solid compound 12 (compound 12 in FIG. 6);
compound 12 (5- ((2- (but-2-yn-1-yloxy) phenyl) amino) -5-oxopentanoic acid), 806 mg,97.8%, purity: 98.7%; 1 H NMR(400MHz,DMSO)δ12.05(s,1H),9.05(s,1H),7.88(d,J＝7.7Hz,1H),7.10-7.04(m,2H),6.91(t,J＝7.5Hz,1H),4.79(s,2H),2.40(t,J＝7.1Hz,2H),2.27(t,J＝7.4Hz,2H),1.83-1.75(m,5H)ppm. 13 C NMR(101MHz,DMSO)δ174.21,170.91,147.99,127.70,124.20,122.71,120.77,112.81,83.83,74.74,56.49,35.17,33.02,20.64,3.20ppm.MS(ESI,m/z):276[M+H] + .
(4) 0.75mmol of Compound 12 was dissolved in 2.0mL of dried N, N-dimethylformamide at room temperature, then 0.75mmol of 2- (7-azabenzotriazol) -N, N, N ', N' -tetramethylurea Hexafluorophosphate (HATU), 0.75mmol of triethylamine and stirring were sequentially added thereto, then 0.3mmol of dihydroxydiammine platinum was added thereto, the reaction was further stirred at room temperature for two days while keeping the reaction flask away from light, and monitored by LC-MS, and thereafter N, N-dimethylformamide was removed by evaporation, and the residue was purified by column chromatography (methanol/dichloromethane (volume ratio: 1:45, 1.0L) to give Compound 15 (Compound 15 in FIG. 6) as a white solid.
Compound 15, 295mg,46.3% with a purity of 97.6%. 1 H NMR(400MHz,DMSO)δ8.94(s,2H),7.93(d,J＝7.3Hz,2H),7.10-7.03(m,4H),6.91(t,J＝7.3Hz,2H),6.54(s,6H),4.80(s,4H),2.41(t,J＝6.3Hz,4H),2.29(t,J＝7.1Hz,4H),1.83-1.75(m,10H)ppm. 13 C NMR(101MHz,DMSO)δ180.40,171.19,147.71,127.74,124.04,122.33,120.75,112.73,83.88,74.74,56.47,35.45,35.05,21.73,3.23ppm.MS(ESI,m/z):848[M+H] + .
Wherein, the dihydroxydichloro diammine platinum is prepared by the following steps: 6.7mmol of cisplatin was added to 60mL of distilled water at room temperature, and 100mL of 30% H was added dropwise thereto 2 O 2 Stirring at 60deg.C for 4 hr, filtering, recrystallizing the filtrate at 2deg.C, filtering, and adding 3mL H 2 O is washed for 2 times, and then vacuum drying is carried out at 60 ℃ to obtain the product. (1.69 g of dihydroxydiammineplatinum dichloride was obtained in a yield of 76%)
Example 2
A method for preparing a compound with an anti-lung cancer effect, which comprises the following steps:
(1) To a solution of 10.0mmol of 3- (BOC-amino) phenol in anhydrous N, N-dimethylformamide (15 mL) at room temperature was added 13.0mmol of Cs 2 CO 3 And stirred for 0.4h, then 12.0mmol of 1-bromo-2-butyne was added dropwise and stirred at room temperature overnight, the reaction was monitored by LC-MS, followed by quenching with 30mL of water, extraction 2 times with 30mL of ethyl acetate, combining the organic phases and washing 2 times with 40mL of water, 1 time with 40mL of brine, drying over 6g of anhydrous sodium sulfate, and purification by column chromatography (ethyl acetate/n-hexane (volume ratio: 1:6,1.2 l)) to give compound 7 as a white solid (compound 7 in fig. 6);
compound 7 (3- (but-2-yn-1-yloxy) phenyl) carbonic acid tert-butyl ester 7, 92.8%; MS (ESI, m/z): 262[ M+H ]] + .
(2) 8.0mmol of Compound 7 was dissolved in 12mL of dried dichloromethane at room temperature, 4mL of trifluoroacetic acid was added thereto and the reaction was stirred at room temperature for 3 hours, the reaction was monitored by LC-MS, the resultant mixture was concentrated and methylene chloride and trifluoroacetic acid were removed, diluted with 30mL of water and 40mL of methylene chloride, the pH of the mixture was adjusted to 8 with 1mol/L of sodium hydroxide solution, followed by separation, the resultant organic phase was washed with 30mL of water and 30mL of brine, and then purified by column chromatography (ethyl acetate/n-hexane (volume ratio: 1:4, 1.2L)) to give a pale brown oily product (Compound 10 in FIG. 6);
compound 10 3- (but-2-yn-1-yloxy) aniline 10.83%; MS (ESI, m/z): 162[ M+H ]] + .
(3) 3.0mmol of the pale brown oily product was dissolved in 15mL of dried dichloromethane at room temperature, 3.0mmol of cyclopentanedioic anhydride was added thereto and stirred at room temperature overnight, the reaction was monitored by LC-MS, the resultant mixture was concentrated and dichloromethane was removed, dichloromethane (5 mL) and n-hexane (15 mL) were then added to form a suspension, followed by filtration, and the cake was washed 2 times with 2mL of n-hexane, followed by vacuum drying to obtain white solid compound 13 (compound 13 in FIG. 6);
compound 13- ((3- (but-2-yn-1-yloxy) phenyl) amino) -5-oxopentanoic acid 816mg,98.8%; the purity is 96.8 percent. 1 H NMR(400MHz,DMSO)δ12.08(s,1H),9.88(s,1H),7.28-7.14(m,3H),6.65-6.62(m,1H),4.68-4.67(m,2H),2.35-2.24(m,4H),1.83-1.77(m,5H)ppm. 13 C NMR(101MHz,DMSO)δ174.19,170.81,157.68,140.42,129.42,111.90,109.09,105.86,83.46,74.81,55.76,35.44,32.98,20.40,3.20ppm.MS(ESI,m/z):276[M+H] + .
(4) 0.75mmol of Compound 13 was dissolved in 2.0mL of dried N, N-dimethylformamide at room temperature, then 0.75mmol of 2- (7-azabenzotriazol) -N, N, N ', N' -tetramethylurea Hexafluorophosphate (HATU), 0.75mmol of triethylamine and stirring for 0.4h were sequentially added thereto, then 0.3mmol of dihydroxydiammine platinum dichloride was added, the reaction was further stirred at room temperature in a tinfoil-wrapped reaction flask protected from light for two days, monitored by LC-MS, N, N-dimethylformamide was removed by evaporation, and the residue was purified by column chromatography (methanol/dichloromethane (volume ratio: 1:9, 1.0L) to give Compound 16 (Compound 16 in FIG. 6) as a white solid.
Compound 16, 358mg,56.3% purity 97.2%. 1 H NMR(400MHz,DMSO)δ9.82(s,2H),7.29-7.17(m,6H),6.64-6.55(m,8H),4.68(s,4H),2.35-2.27(m,8H),1.83-1.73(m,10H)ppm. 13 C NMR(101MHz,DMSO)δ180.32,171.14,157.67,140.42,129.40,111.89,109.05,105.83,83.45,74.81,55.76,35.73,35.00,21.54,3.21ppm.MS(ESI,m/z):848[M+H] + .
Wherein, the dihydroxydichloro diammine platinum is prepared by the following steps: 6.7mmol of cisplatin was added to 60mL of distilled water at room temperature, and 100mL of 30% H was added dropwise thereto 2 O 2 Stirring at 50deg.C for 5 hr, filtering, recrystallizing the filtrate at 0deg.C, filtering, and adding 3mL H 2 O is washed for 2 times, and then vacuum drying is carried out at 50 ℃.
Example 3
A method for preparing a compound with an anti-lung cancer effect, which comprises the following steps:
(1) To a solution of 10.0mmol of 4- (BOC-amino) phenol in anhydrous N, N-dimethylformamide (15 mL) at room temperature was added 13.0mmol Cs 2 CO 3 And stirred for 0.6h, then 12.0mmol of 1-bromo-2-butyne was added dropwise and stirred at room temperature overnight, the reaction was monitored by LC-MS, followed by quenching with 30mL of water, extraction 2 times with 30mL of ethyl acetate, combining the organic phases and washing 2 times with 40mL of water, 1 time with 40mL of brine, drying over 6g of anhydrous sodium sulfate, and purification by column chromatography (ethyl acetate/n-hexane (volume ratio: 1:6,1.2 l)) to give compound 8 (compound 8 in fig. 6) as a white solid;
compound 8 (4- (but-2-yn-1-yloxy) phenyl) carbonic acid tert-butyl ester 8, 93.5%; MS (ESI, m/z): 262[ M+H ]] + .
(2) 8.0mmol of Compound 8 was dissolved in 12mL of dried dichloromethane at room temperature, 4mL of trifluoroacetic acid was added thereto and reacted at room temperature with stirring for 5 hours, the reaction was monitored by LC-MS, the resultant mixture was concentrated and methylene chloride and trifluoroacetic acid were removed, diluted with 30mL of water and 40mL of methylene chloride, the pH of the mixture was adjusted to 9 with 1mol/L of sodium hydroxide solution, followed by separation, the resultant organic phase was washed with 30mL of water and 30mL of brine, and then purified by column chromatography (ethyl acetate/n-hexane (volume ratio: 1:4, 1.2L)) to give a pale brown oily product (Compound 11 in FIG. 6);
compound 11, 4- (but-2-yn-1-yloxy) aniline 11, 92.4%; MS (ESI, m/z): 162[ M+H ]] + .
(3) 3.0mmol of the pale brown oily product was dissolved in 15mL of dried dichloromethane at room temperature, 3.0mmol of cyclopentanedioic anhydride was added thereto and stirred at room temperature overnight, the reaction was monitored by LC-MS, the resultant mixture was concentrated and dichloromethane was removed, dichloromethane (5 mL) and n-hexane (15 mL) were then added to form a suspension, followed by filtration, and the cake was washed 2 times with 2mL of n-hexane, followed by vacuum drying to obtain white solid compound 14 (compound 14 in FIG. 6);
compound 14- ((4- (but-2-yn-1-yloxy) phenyl) amino) -5-oxopentanoic acid 14, 802mg,97.1% purity 99.1%. 1 H NMR(400MHz,DMSO)δ12.07(s,1H),9.76(s,1H),7.49-7.47(m,2H),6.90-6.87(m,2H),4.67(d,J＝2.3Hz,2H),2.32-2.24(m,4H),1.82-1.75(m,5H)ppm. 13 C NMR(101MHz,DMSO)δ174.21,170.27,153.14,132.92,120.55,114.82,83.37,74.93,55.99,35.27,33.02,20.54,3.17ppm.MS(ESI,m/z):276[M+H] + .
(4) 0.75mmol of compound 14 was dissolved in 2.0mL of dried N, N-dimethylformamide at room temperature, then 0.75mmol of 2- (7-azabenzotriazol) -N, N, N ', N' -tetramethylurea Hexafluorophosphate (HATU), 0.75mmol of triethylamine and stirring for 0.6h were sequentially added thereto, then 0.3mmol of dihydroxydiammine platinum dichloride was added, the reaction was further stirred at room temperature in a tinfoil-wrapped reaction flask protected from light for two days, monitored by LC-MS, N, N-dimethylformamide was removed by evaporation, and the residue was purified by column chromatography (methanol/dichloromethane (volume ratio: 1:9, 1.0L) to give compound 17 (compound 17 in FIG. 6) as a white solid.
Compound 17, 377mg,59.2%, purity 98.5%. 1 H NMR(400MHz,DMSO)δ9.68(s,2H),7.49(d,J＝9.0Hz,4H),6.88(d,J＝9.0Hz,4H),6.54(s,6H),4.67(d,J＝2.3Hz,4H),2.29(q,J＝7.4Hz,8H),1.82-1.73(m,10H)ppm. 13 C NMR(101MHz,DMSO)δ180.34,170.58,153.11,132.91,120.53,114.79,83.35,74.92,55.97,35.56,35.04,21.66,3.16ppm.MS(ESI,m/z):848[M+H] + .
Wherein, the dihydroxydichloro diammine platinum is prepared by the following steps: 6.7mmol of cisplatin was added to 60mL of distilled water at room temperature, and 100mL of 30% H was added dropwise thereto 2 O 2 Stirring at 70deg.C for 3 hr, filtering, recrystallizing the filtrate at 4deg.C, filtering, and adding 3mL H 2 O is washed for 2 times, and then vacuum drying is carried out at 70 ℃.
Example 4
A method for preparing a compound with an anti-lung cancer effect, which comprises the following steps:
(1) The procedure of step (1) of example 1 was repeated except that 1-bromo-2-butyne in step (1) was changed to 3-bromopropene, and the procedure was repeated in the same manner as in step (1) of example 1 to obtain compound 18 in FIG. 6;
compound 18 (2- (allyloxy) phenyl) carbonate, 92.9%; MS (ESI, m/z): 250[ M+H ]] + .
(2) The same as in step (2) of example 1, compound 21 in fig. 6 was obtained;
compound 21, 2- (allyloxy) aniline, 75.8%; MS (ESI, m/z): 150[ M+H ]] + .
(3) The same procedure as in step (3) of example 1 gave compound 24 of FIG. 6;
compound 24- ((2- (allyloxy) phenyl) amino) -5-oxopentanoic acid, 779mg,98.1%, purity:99.3%. 1 H NMR(400MHz,DMSO)δ12.05(s,1H),8.99(s,1H),7.85(d,J＝7.5Hz,1H),7.06-6.87(m,3H),6.11-6.02(m,1H),5.44-5.24(m,2H),4.62(d,J＝4.3Hz,2H),2.41(t,J＝6.9Hz,2H),2.27(t,J＝7.3Hz,2H),1.83-1.76(m,2H)ppm. 13 C NMR(101MHz,DMSO)δ174.17,170.80,148.90,133.69,127.51,124.42,122.80,120.37,117.35,112.66,68.87,35.19,32.98,20.64ppm.MS(ESI,m/z):264[M+H] + .
(4) Compound 27 of fig. 6 was obtained in the same manner as in step (4) of example 1.
Compound 27, 238mg,38.5% purity 97.2%. 1 H NMR(400MHz,DMSO)δ8.88(s,2H),7.90(d,J＝7.5Hz,2H),7.05-7.01(m,4H),6.88(t,J＝7.0Hz,2H),6.53(s,6H),6.10-6.04(m,2H),5.44-5.25(m,4H),4.62(d,J＝4.6Hz,4H),2.41(t,J＝6.8Hz,4H),2.29(t,J＝7.3Hz,4H),1.80-1.75(m,4H)ppm. 13 C NMR(101MHz,DMSO)δ180.41,171.11,148.63,133.69,127.57,124.26,122.39,120.37,117.51,112.60,68.91,35.49,35.06,21.74ppm.MS(ESI,m/z):824[M+H] + .
Wherein, the preparation method of the dihydroxydiammine platinum is the same as that of the example 1.
Example 5
A method for preparing a compound with an anti-lung cancer effect, which comprises the following steps:
(1) The procedure of example 1, step (1), was followed except that 1-bromo-2-butyne in step (1) was changed to 3-bromopropene, 2- (BOC-aminomethyl) phenol was changed to 3- (BOC-amino) phenol, and the residue was the same as in example 1, step (1), to give compound 19 in FIG. 6;
compound 19 (3- (allyloxy) phenyl) carbonate, 96.1%; MS (ESI, m/z): 250[ M+H ]] + .HRMS(ESI,m/z):[M+Na] + Theoretical value C 14 H 19 NNaO 3 + 272.1257, found 272.1254.
(2) The same procedure as in step (2) of example 1 gave compound 22 of FIG. 6;
compound 22, 3- (allyloxy) aniline 22, 88.2%; MS (ESI, m/z): 150[ M+H ]] + .HRMS(ESI,m/z):[M+H] + Theoretical value C 9 H 12 NO + 150.0913, found 150.0915.
(3) The same as in step (3) of example 1, compound 25 in fig. 6 was obtained;
compound 25- ((3- (allyloxy) phenyl) amino) -5-oxopentanoic acid, 761mg,96.3%, purity:97.2%. 1 H NMR(400MHz,DMSO)δ12.08(s,1H),9.86(s,1H),7.32(s,1H),7.19-7.08(m,2H),6.62-6.60(m,1H),6.07-5.98(m,1H),5.40-5.23(m,2H),4.51
-4.50(m,2H),2.35-2.24(m,4H),1.82-1.75(m,2H)ppm. 13 C NMR(101MHz,DMSO)δ174.19,170.81,158.42,140.45,133.72,129.44,117.38,111.50,109.11,105.66,68.07,35.45,32.98,20.40ppm.MS(ESI,m/z):264[M+H] + .
(4) The same procedure as in step (4) of example 1 gave compound 28 of FIG. 6.
Compound 28, 268mg,43.4% purity 97.0%. 1 H NMR(400MHz,DMSO)δ9.80(s,2H),7.34(s,2H),7.19-7.10(m,4H),6.62-6.55(m,8H),6.08-5.99(m,2H),5.38(d,J＝17.3Hz,2H),5.25(d,J＝9.7Hz,2H),4.52(s,4H),2.32-2.29(m,8H),1.78-1.75(m,4H)ppm. 13 C NMR(101MHz,DMSO)δ180.33,171.14,158.41,140.45,133.71,129.43,117.38,111.50,109.11,105.62,68.07,35.74,35.00,21.54ppm.MS(ESI,m/z):824[M+H] + .
Wherein, the preparation method of the dihydroxydiammine platinum is the same as that of the example 1.
Example 6
A method for preparing a compound with an anti-lung cancer effect, which comprises the following steps:
(1) The procedure of example 1, step (1), was followed except that 1-bromo-2-butyne in step (1) was changed to 3-bromopropene, 2- (BOC-aminomethyl) phenol was changed to 4- (BOC-amino) phenol, and the residue was the same as in example 1, step (1), to give compound 20 in FIG. 6;
compound 20 (4- (allyloxy) phenyl) carbonate, 93.5%; MS (ESI, m/z): 250[ M+H ]] + .
(2) The same as in step (2) of example 1, compound 23 in fig. 6 was obtained;
compound 23, 4- (allyloxy) aniline 23, 91.6%; MS (ESI, m/z): 150[ M+H ]] + .
(3) The same as in step (3) of example 1, compound 26 in fig. 6 was obtained;
compound 26- ((4- (allyloxy) phenyl) amino) -5-oxopentanoic acid, 769mg,97.3%, purity:99.8%. 1 H NMR(400MHz,DMSO)δ12.07(s,1H),9.74(s,1H),7.47(d,J＝9.0Hz,2H),6.87(d,J＝9.0Hz,2H),6.07-5.97(m,1H),5.40-5.22(m,2H),4.51(d,J＝5.2Hz,2H),2.32-2.24(m,4H),1.83-1.75(m,2H)ppm. 13 C NMR(101MHz,DMSO)δ174.20,170.21,153.93,133.90,132.61,120.58,117.31,114.63,68.32,35.28,33.02,20.54ppm.MS(ESI,m/z):264[M+H] + .
(4) The same procedure as in step (4) of example 1 gave compound 29 in FIG. 6.
Compound 29, 393mg,63.5%, purity 99.1%. 1 H NMR(400MHz,DMSO)δ9.67(s,2H),7.48(d,J＝8.9Hz,4H),6.87(d,J＝9.0Hz,4H),6.54(s,6H),6.07-5.97(m,2H),5.40-5.22(m,4H),4.50(d,J＝5.2Hz,4H),2.31-2.26(m,8H),1.80-1.73(m,4H)ppm. 13 C NMR(101MHz,DMSO)δ180.36,170.55,153.91,133.90,132.61,120.58,117.32,114.62,68.32,35.58,35.05,21.68ppm.MS(ESI,m/z):824[M+H] + .
Wherein, the preparation method of the dihydroxydiammine platinum is the same as that of the example 1.
Experimental example 1
Compounds 15, 16, 17 and compounds 27, 28, 29 in fig. 6 inhibit lung cancer a549, a549R and HCC827 cell proliferation:
lung cancer cells a549, a549R (cisplatin resistant cells) and HCC827 were seeded into 96-well plates at 3000 cells/well and placed in CO 2 In incubator (37 ℃, 5% CO) 2 ) Culturing overnight. Compounds 15, 16, 17 and 27, 28, 29 were added to the experimental groups to give final concentrations of 0.2, 0.4, 0.8, 1.6, 3.2, 6.4, 12.5, 25, 50. Mu.M, respectively, and the control group was added with corresponding volumes of DMSO. After 48 hours of further incubation, 20. Mu.L MTT solution was added to each well and incubation continued for 4 hours, medium was aspirated off and 200. Mu.L DMSO reagent was added, shaking (shaking at 300rpm for 10 min); OD values at 570nm were read using a microplate reader (BioTek station 5), cell growth inhibition = (1-OD experiment/OD control) ×100%, and IC50 values were calculated using Graphpad Prism 8, and the results are shown in table 1.
TABLE 1 IC50 values (μM) of compounds for lung cancer cells
Compounds of formula (I) A549 A549R HCC827
15 ＞50 ＞50 ＞50
16 3.17±0.07 2.01±0.28 1.06±0.04
17 1.98±0.05 3.23±0.91 2.76±0.12
27 ＞50 ＞50 ＞50
28 2.36±0.19 1.52±0.04 1.37±0.05
29 2.03±0.19 2.67±0.38 1.72±0.12
Experimental example 2
Compounds 16, 28 in fig. 6 inhibited lung cancer cell a549 and a549R clone formation:
a549 and a549R cells were counted and inoculated into 6-well plates at 1000 cells per well, and after 24h inoculation 2 μm compound 1 (cisplatin), 13, 25, 16 or 28, respectively, were added and placed at 37 ℃ in 5% co 2 Culturing in an incubator for about 14d; the supernatant was discarded, the cells were fixed with 4% paraformaldehyde, stained with crystal violet for 30min, and washed 3 times with pbs for 2min each. And scanning the experimental result by a scanner, and carrying out statistical analysis. As shown in FIG. 1, the compounds 16 and 28 have the ability to significantly inhibit the formation of lung cancer cell clones (P < 0.01) compared with cisplatin and DMSO groups, and the ligand compound 13 and compound 25 have no effect on the formation of lung cancer cell clonesSignificantly inhibiting activity.
Experimental example 3
Flow cytometry analysis compounds 16, 28 in fig. 6 promote apoptosis:
taking A549 and A549R cells in logarithmic growth phase, digesting, counting, and obtaining 2×10 6 Inoculating the cells/well into 6-well plate, and CO 2 Culturing in an incubator for 24 hours; adding the compounds 16 and 28 to make the final concentration of the compounds 2 mu M respectively, setting 3 compound holes, and continuously culturing for 24 hours; collecting the culture medium containing the drug, collecting cells in the same EP tube, centrifuging at 1000r/min for 5min, discarding supernatant, and adjusting cell concentration to 10 with Binding buffer 6 individual/mL; 100 mu L of 10 6 Cell suspension at a concentration of individual/mL, 5. Mu.L of annexin V-FITC and 5. Mu.L of PI were added, and left at room temperature for 15min in the absence of light; after staining in dark for 30min, the cells were checked for apoptosis by the machine, 10000 cells were checked per sample. The results are shown in figure 2, where the number of apoptosis induced by compounds 16, 28 is significantly higher than in cisplatin and control groups.
Experimental example 4
Compounds 16, 28 affect apoptosis-related protein expression:
a549 cells were plated in 6cm dishes, CO 2 Culturing in an incubator overnight; compounds 16, 28 and cisplatin were added to give final concentrations of 2. Mu.M, and the culture was continued for 48 hours, after which cells were collected. Adding RIPA lysate (containing protease inhibitor) to break cells, centrifuging at 15000rpm for 30min, and collecting supernatant; protein supernatant is quantified by BCA method, and 30 mug total protein is loaded for SDS-PAGE electrophoresis; transferring the protein on the PAGE gel to a PVDF membrane by adopting a wet transfer method, then sealing 5% skimmed milk for 2 hours at room temperature, and washing with TBST for 5 times each for 2 minutes; bax, clear-PARP antibodies (1:1000) were incubated overnight at 4deg.C, TBST washed 5 times for 2min each; the dilution ratio of the secondary antibody is 1:20000, the secondary antibody is incubated for 1h at room temperature, and the secondary antibody is washed for 5 times by TBST for 2min each time; and detecting the target strip by using an LI-COR odyley laser scanner, and storing the picture. As shown in FIG. 3, compounds 16 and 28, after treating cells, cause up-regulation of apoptosis proteins Bax and clear-PARP expression, and promote apoptosis.
Experimental example 5
Compounds 16, 28 inhibit lung cancer A549 cell subcutaneous tumor growth:
female BALB/c-nu mice of 4 weeks old were housed in SPF-class animal houses and inoculated subcutaneously on the left upper forelimbs of the mice 10 7 A549 cells, waiting for tumor size to be about 100mm 3 At the time, mice were divided into: control group, cisplatin 5mg/kg, compound 16 5mg/kg group and compound 28 5mg/kg group, and administration was performed. The administration mode is as follows: administering to the abdominal cavity; dosing volume: 100. Mu.L; frequency of administration: 2 days/time; number of administrations: 4 times. And at the same time as dosing, the mice body weight was recorded. Mice were sacrificed on day 21 after the first dose, tumors were removed for photography and weighed. The experimental results are shown in fig. 4 and 5, the compounds 16 and 28 can inhibit the growth of the A549 subcutaneous tumor, have obvious anti-tumor activity, and the weight shows that the compounds 16 and 28 have no obvious toxic or side effect.
While specific embodiments of the invention have been described in detail in connection with the examples, it should not be construed as limiting the scope of protection of the patent. Various modifications and variations which may be made by those skilled in the art without the creative effort are within the scope of the patent described in the claims.

Claims (8)

1. The compound with the lung cancer resisting effect is characterized by having the structural formula:
2. the method for preparing a compound having an anti-lung cancer effect according to claim 1, comprising the steps of:
(1) Dissolving a compound shown in a formula I in an organic solvent, adding alkali, stirring at room temperature for reaction for 0.4-0.6 h, dropwise adding 1-bromo-2-butyne or 3-bromopropene, stirring at room temperature overnight, and sequentially extracting, washing, drying and purifying to obtain a compound shown in a formula II;
wherein R is 3 Is that
(2) Dissolving a compound shown in a formula II in an organic solvent, adding trifluoroacetic acid, stirring at room temperature for reaction for 3-5 h, and then sequentially concentrating, alkalizing, separating liquid, washing and purifying to obtain the compound shown in a formula III;
(3) Dissolving a compound shown in a formula III in an organic solvent, adding cyclopentanedioic anhydride, stirring overnight at room temperature, and sequentially concentrating, filtering, washing and drying to obtain a compound shown in a formula IV;
(4) Dissolving a compound shown in a formula IV in an organic solvent, adding 2- (7-aza-benzotriazol) -N, N, N ', N' -tetramethyl urea hexafluorophosphate and triethylamine, stirring at room temperature for reaction for 0.4-0.6 h, adding dihydroxydichloro diammine platinum, stirring at room temperature for reaction for two days in dark, concentrating, and purifying to obtain the compound.
3. The preparation method according to claim 2, characterized in that: in the step (1), the mol ratio of the compound shown in the formula I, alkali, 1-bromo-2-butyne or 3-bromopropene is 9-11: 12-14: 11 to 13; in the step (1), the purification is column chromatography, and the volume ratio of the used reagents is 1: 6-20 of ethyl acetate and n-hexane.
4. The preparation method according to claim 2, characterized in that: the dosage ratio of the compound shown as the formula II to trifluoroacetic acid in the step (2) is 8mmol: 3-5 mL; in the step (2), the purification is column chromatography, and the volume ratio of the used reagents is 1:4 to 9 of ethyl acetate and n-hexane.
5. The preparation method according to claim 2, characterized in that: in the step (3), the molar ratio of the compound shown in the formula III to the cyclopentanedioanhydride is 2-4: 3.
6. the preparation method according to claim 2, characterized in that: in the step (4), the mol ratio of the compound shown in the formula IV, 2- (7-aza-benzotriazol) -N, N, N ', N' -tetramethyl urea hexafluorophosphate, triethylamine and dihydroxy dichloro diammine platinum is 0.7-0.8: 0.7 to 0.8:0.7 to 0.8:0.2 to 0.4; in the step (4), the purification is column chromatography, and the volume ratio of the used reagents is 1:9 to 99 of methanol and methylene dichloride.
7. The method according to claim 2 or 6, wherein the dihydroxydiammine platinum is prepared by the steps of: dropwise adding H into cisplatin water solution at room temperature 2 O 2 Stirring at 50-70 deg.c for 3-5 hr, filtering, re-crystallizing at 0-4 deg.c, filtering, washing and drying.
8. The use of a compound having an anti-lung cancer effect according to claim 1 for the preparation of an anti-lung cancer medicament.
CN202210688316.9A 2022-06-17 2022-06-17 Compound with anti-lung cancer effect and preparation method and application thereof Active CN114940692B (en)

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Publication number Priority date Publication date Assignee Title
CN105622674A (en) * 2016-02-29 2016-06-01 东南大学 Tetravalent platinum complex with bioactive group and preparation method of tetravalent platinum complex
WO2019166033A2 (en) * 2018-03-02 2019-09-06 天津谷堆生物医药科技有限公司 Vitamin c-platinum complex, intermediate thereof, preparation method, pharmaceutical composition and use
CN113072588A (en) * 2021-03-19 2021-07-06 中国人民解放军空军军医大学 Tetravalent platinum complex containing artesunate and preparation method and application thereof
CN113072595A (en) * 2021-06-03 2021-07-06 江苏南创化学与生命健康研究院有限公司 Low-toxicity Pt complex and preparation method and application thereof

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105622674A (en) * 2016-02-29 2016-06-01 东南大学 Tetravalent platinum complex with bioactive group and preparation method of tetravalent platinum complex
WO2019166033A2 (en) * 2018-03-02 2019-09-06 天津谷堆生物医药科技有限公司 Vitamin c-platinum complex, intermediate thereof, preparation method, pharmaceutical composition and use
CN113072588A (en) * 2021-03-19 2021-07-06 中国人民解放军空军军医大学 Tetravalent platinum complex containing artesunate and preparation method and application thereof
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