CN111548355B - Artemisia apiacea sulfone-piperazine-furanone derivative and preparation method and application thereof - Google Patents
Artemisia apiacea sulfone-piperazine-furanone derivative and preparation method and application thereof Download PDFInfo
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Abstract
The embodiment of the invention discloses a sweet wormwood sulfone-piperazine-furanone derivative and a preparation method and application thereof, wherein the derivative has the following general formula:
wherein R is
Or
And X is Br or Cl. According to the sweet wormwood sulfone-piperazine-furanone derivative, a plurality of hydrogen bonds or ionic bonds are formed by adding piperazine so as to improve the biological activity of the derivative, the solubility and the acid-base balance of the derivative are adjusted, the pharmacokinetics of the derivative is promoted, and the antitumor activity of the prepared derivative can be remarkably improved by adding furanone, so that the derivative can remarkably inhibit the growth of tumor cells.
Description
Technical Field
The embodiment of the invention relates to the technical field of sweet wormwood sulfone derivatives, and in particular relates to a sweet wormwood sulfone-piperazine-furanone derivative and a preparation method and application thereof.
Background
Liver cancer, a malignant tumor of the liver, can be divided into primary and secondary types. The primary liver malignant tumor originates from the epithelium or mesenchymal tissue of the liver, the former is called primary liver cancer, which is a malignant tumor with high incidence and great harm in China; the latter is called sarcoma, and is less common than primary liver cancer. Secondary or metastatic liver cancer refers to the invasion of malignant tumors of multiple organ origins in the whole body to the liver. Liver metastasis of malignant tumors of stomach, biliary tract, pancreas, colon, ovary, uterus, lung, and breast is common.
Artemisinin and its derivatives (such as artesunone) have good antimalarial activity, but the research on its anti-tumor activity is relatively few, and the artemisinin and its derivatives (such as artesunone) are clinically applied for many years, but still have the disadvantages of poor oil solubility and water solubility, poor thermal stability, easy decomposition due to the influence of damp, hot and reducing substances, high clinical recurrence rate, poor treatment effect and the like, so that the application is limited.
Disclosure of Invention
Therefore, the embodiment of the invention provides an arteannuin sulfone-piperazine-furanone derivative, which aims to solve the problems of high clinical recurrence rate and poor treatment effect caused by easy decomposition of artemisinin and derivatives thereof in the prior art.
In order to achieve the above object, the embodiments of the present invention provide the following technical solutions:
according to a first aspect of embodiments of the present invention there is provided a sulphone-piperazine-furanone derivative of the formula:
wherein R is
And X is Br or Cl.
The invention takes piperazine as a connector, introduces a furanone structure into artemisia apiacea sulfone molecules to prepare the artemisia apiacea sulfone-piperazine-furanone derivative, forms a plurality of hydrogen bonds or ionic bonds through the addition of piperazine to improve the biological activity of the derivative, regulates the solubility and the acid-base balance of the derivative, promotes the pharmacokinetics of the derivative, and can remarkably improve the anti-tumor activity of the prepared derivative through the addition of furanone, so that the derivative can remarkably inhibit the growth of tumor cells, especially inhibit the growth of human liver cancer cells (SMMC-7721 and MHCC 97H).
According to a second aspect of embodiments of the present invention, there is provided a method for preparing the above derivative, the method comprising the steps of:
(a) dissolving sweet wormwood sulfone-piperazine and halogenated furanone in acetonitrile to obtain a mixture;
(b) adding diisopropylethylamine into the mixture, and reacting under the condition of stirring;
(c) and (3) after the reaction is finished, evaporating the solvent, separating and purifying to obtain the derivative.
The method takes diisopropylethylamine as an acid-binding agent and acetonitrile as a reaction solvent, can prepare the sweet wormwood sulfone-piperazine-furanone derivative at high efficiency under mild conditions, is simple to operate, does not need to be carried out under the harsh anhydrous and anaerobic conditions, does not contain a metal reagent, is environment-friendly and has high atom utilization rate.
Further, the sweet wormwood sulfone-piperazine is not strictly limited, and can be prepared by the following method:
adding 3.5g of anhydrous thiomorpholine and 35mL of dry dichloromethane into a 250mL three-neck flask, and stirring at room temperature until the anhydrous thiomorpholine and the dry dichloromethane are completely dissolved; adding dihydroartemisinin DHA (2g, 7mmol) and 25mL of dry dichloromethane into a 200mL three-neck flask under the protection of Ar gas, stirring at room temperature for 5min, then adding 65 mu L of dry dimethyl sulfoxide DMSO, continuing stirring for 2min, and then slowly dropwise adding 0.6-0.7mL of oxalyl chloride; slowly dripping the dichloromethane solution of thiomorpholine into the reaction solution, reacting at room temperature overnight, washing the reaction solution with 20mL saturated sodium carbonate and 20mL saturated sodium chloride after the reaction is finished, extracting the water phase with 3x 25mL ethyl acetate, combining the organic phases, and adding anhydrous Na2SO4Drying, vacuum filtering, removing solvent under reduced pressure, and separating with silica gel column chromatography to obtain artemisinin-thiomorpholine; a100 mL flask was charged with artemisinin-thiomorpholine (1.87g, 5.1mmol), 100mg sodium tungstate, 60mL of a mixture of tetrahydrofuran and water (V: 4:1), stirred at room temperature for 5min, and then 1.5mL hydrogen peroxide (33%) was added over 2h, followed by TLC, after disappearance of the starting material point, 100mL EA (ethyl acetate) was added to dilute the reaction, washed with 3X 30mL of saturated sodium chloride, and washed with anhydrous Na2SO4Drying the organic phase, performing suction filtration under reduced pressure, removing the solvent by rotary removal under reduced pressure, and performing silica gel column chromatography to obtain sweet wormwood sulfone; a100 mL flask was charged with 1, 6-hexanediol (2.36g, 20mmol), t-butyldimethylsilyl chloride TBSCl (1.8g, 12mmol), anhydrous imidazole (2.1g, 30mmol) and 40mL of ultra-dry N, N-dimethylformamide, stirred at room temperature overnight, after completion of the reaction, the reaction was diluted with 40mL of water and 80mL of ethyl acetate, washed with 3X 35mL of saturated sodium chloride, and washed with anhydrous Na2SO4Drying the organic phase, performing vacuum filtration, performing vacuum rotary removal of the solvent, and performing silica gel column chromatography to obtain dimethyl tert-butyl siloxy hexanol; a100 mL flask was charged with dimethyl tert-butylsiloxanyl hexanol (1.6g, 6mmol), triphenyl phosphine (1.83g, 7mmol), anhydrous imidazole (0.84g,12mmol) and 40mL dry THF, stirred at room temperature until the starting material was completely dissolved, after which elemental iodine (1.78g, 7mmol) was slowly addedmmol), reaction at room temperature in the dark overnight, after the reaction is finished, diluting the reaction solution with 60mL of ethyl acetate, washing the mixture with 25mL of saturated sodium thiosulfate, then washing with 2X 40mL of saturated sodium chloride, and anhydrous Na2SO4Drying the organic phase, performing vacuum filtration, removing the solvent by rotary removal under reduced pressure, and performing silica gel column chromatography to obtain dimethyl tert-butyl siloxy iodohexane; adding dry diisopropylamine (0.63g, 6.3mmol), about 1mg of 2, 2-bipyridine and 10mL of dry THF into a 100mL two-necked flask at-30 ℃ in a stream of anhydrous Ar gas, stirring until completely dissolved, adding 4mL of n-butyllithium (1.6M, n-hexane solution), continuing to stir for 25-30min, then decreasing to-78 ℃, adding 10mL of dry tetrahydrofuran solution dissolved with artesunone (1.2g, 3mmol), continuing to stir for 45min, then adding 10mL of dry tetrahydrofuran solution dissolved with compound dimethyl tert-butyl silica iodohexane (1.19g), continuing to react for 3h, then gradually increasing to room temperature, after the reaction is finished, diluting the reaction solution with 80mL of ethyl acetate, washing with 40mL of saturated ammonium chloride, washing with 2X 40mL of saturated sodium chloride, washing with anhydrous Na2SO4Drying the organic phase, performing vacuum filtration, removing the solvent by rotary removal under reduced pressure, and performing silica gel column chromatography to obtain the artesunone derivative; dissolving 0.9g of sweet wormwood sulfone derivative and 1.42g of tetrabutylammonium fluoride in 40mL of THF (tetrahydrofuran) in a 50mL flask, reacting at room temperature overnight, adding 100mL of ethyl acetate to dilute the reaction after the reaction is finished, washing with 2x 40mL of saturated sodium chloride, and washing with anhydrous Na2SO4Drying the organic phase, carrying out suction filtration under reduced pressure, carrying out rotary removal on the solvent under reduced pressure to obtain a yellow oily substance, dissolving the oily substance by using 30mL of dry tetrahydrofuran, adding triphenylphosphine (0.4g, 1.52mmol) and anhydrous imidazole (0.21g, 3mmol), stirring at room temperature until the oily substance is completely dissolved, then adding elementary iodine (0.39g, 1.52mmol), stirring at room temperature in a dark place overnight, after the reaction is finished, diluting the reaction solution by using 60mL of ethyl acetate, washing by using 25mL of saturated sodium thiosulfate, washing by using 2x 25mL of saturated sodium chloride, and washing by using anhydrous Na2SO4Drying the organic phase, performing suction filtration under reduced pressure, removing the solvent under reduced pressure, and performing silica gel column chromatography to obtain sweet wormwood sulfone iodide; a flask was charged with 0.46g of Artemisia apiacea sulfone iodide, 0.43g of anhydrous piperazine, about 0.2mL of diisopropylethylamine, dissolved completely with 20mL of dry tetrahydrofuran and 1mL of dry methanol under stirring at room temperature, gradually warmed to 61 deg.C, and a white precipitate formedReacting for 4h, washing the reaction solution with a mixed solution of 15mL saturated sodium carbonate and 20mL saturated sodium chloride after the reaction is finished, extracting the aqueous phase with 2x 25mL ethyl acetate, combining the organic phases, and anhydrous Na2SO4Drying the organic phase, performing suction filtration under reduced pressure, removing the solvent by rotary removal under reduced pressure, and performing silica gel column chromatography to obtain the sweet wormwood sulfone-piperazine.
Furthermore, the mol ratio of the sweet wormwood sulfone-piperazine to the halogenated furanone is 1 to (0.8-1.2).
Further, the molar ratio of the diisopropylethylamine to the sweet wormwood sulphone-piperazine is (2.8-3.2) to 1.
Further, the reaction temperature is room temperature, and the reaction time is 2-4 h.
In the present invention, by further limiting the above parameters, the reaction between the raw materials can be promoted more effectively, and the yield can be improved.
Further, the halogenated furanone is selected from any one of 3, 4-dichloro-5-methoxy furanone, 3, 4-dichloro-5-menthoxy furanone, 3, 4-dichloro-5-borneoxy furanone, 3, 4-dibromo-5-methoxy furanone, 3, 4-dibromo-5-menthoxy furanone and 3, 4-dibromo-5-borneoxy furanone.
Further, the separation and purification mode is silica gel column chromatography, and a developing agent adopted by the silica gel column chromatography is a mixture of petroleum ether and ethyl acetate, wherein the volume ratio of the petroleum ether to the ethyl acetate is (2-20) to 1.
According to a third aspect of the embodiments of the present invention, there is provided a use of the above derivative or the derivative obtained by the above preparation method in preparing an antitumor drug.
Further, the tumors include liver cancer, breast cancer, prostate cancer and colon cancer.
According to a fourth aspect of the embodiments of the present invention, there is provided an anti-liver cancer pharmaceutical preparation, comprising a therapeutically effective amount of the above-mentioned derivatives or the derivatives prepared by the above-mentioned preparation method.
Further, the pharmaceutical preparation also comprises ferrous sulfate; the anti-tumor effect of the derivative can be obviously improved by adding ferrous sulfate.
The embodiment of the invention has the following advantages:
(1) the invention takes piperazine as a connector, introduces a furanone structure into artemisia apiacea sulfone molecules to prepare the artemisia apiacea sulfone-piperazine-furanone derivative, forms a plurality of hydrogen bonds or ionic bonds through the addition of piperazine to improve the biological activity of the derivative, regulates the solubility and the acid-base balance of the derivative, promotes the pharmacokinetics of the derivative, and can remarkably improve the anti-tumor activity of the prepared derivative through the addition of furanone, so that the derivative can remarkably inhibit the growth of tumor cells, especially inhibit the growth of human liver cancer cells (SMMC-7721 and MHCC 97H).
(2) The preparation method provided by the invention has the advantages that diisopropylethylamine is used as an acid-binding agent, acetonitrile is used as a reaction solvent, the sweet wormwood sulfone-piperazine-furanone derivative can be efficiently prepared under mild conditions, the preparation method is simple to operate, the preparation method does not need to be carried out under harsh anhydrous and anaerobic conditions, no metal reagent is used, the preparation method is environment-friendly, and the atom utilization rate is high.
Drawings
In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings used in the description of the embodiments or the prior art will be briefly described below. It should be apparent that the drawings in the following description are merely exemplary, and that other embodiments can be derived from the drawings provided by those of ordinary skill in the art without inventive effort.
FIG. 1 shows the preparation of sulphone-piperazine-furanone derivatives of Artemisia annua prepared in example 1 of the present invention1HNMR spectrogram;
FIG. 2 shows the preparation of sulphone-piperazine-furanone derivatives of Artemisia annua prepared in example 1 of the present invention13CNMR spectrogram;
FIG. 3 is a mass spectrum of the Artemisia apiacea sulfone-piperazine-furanone derivative prepared in example 1 of the present invention;
FIG. 4 shows the preparation of sulfone-piperazine-furanone derivatives of Artemisia annua prepared in example 2 of the present invention1HNMR spectrogram;
FIG. 5 is a drawing showingThe method for preparing the sweet wormwood sulfone-piperazine-furanone derivative in the embodiment 213CNMR spectrogram;
FIG. 6 is a mass spectrum of the Artemisia apiacea sulfone-piperazine-furanone derivatives prepared in example 2 of the present invention;
FIG. 7 shows the preparation of the sulphone-piperazine-furanone derivatives of Artemisia annua prepared in example 3 of the present invention1HNMR spectrogram;
FIG. 8 shows the preparation of the sulphone-piperazine-furanone derivatives of Artemisia annua prepared in example 3 of the present invention13CNMR spectrogram;
FIG. 9 is a mass spectrum of the sulphone-piperazine-furanone derivative of Artemisia annua prepared in example 3 of the present invention;
FIG. 10 shows the preparation of sulphone-piperazine-furanone derivatives of Artemisia annua according to example 4 of the present invention1HNMR spectrogram;
FIG. 11 shows the preparation of sulphone-piperazine-furanone derivatives of Artemisia annua according to example 4 of the present invention13CNMR spectrogram;
FIG. 12 is a mass spectrum of the sulphone-piperazine-furanone derivative of Artemisia annua prepared in example 4 of the present invention;
FIG. 13 shows the preparation of sulphone-piperazine-furanone derivatives of Artemisia annua prepared in example 5 of the present invention1HNMR spectrogram;
FIG. 14 shows the preparation of sulphone-piperazine-furanone derivatives of Artemisia annua prepared in example 5 of the present invention13CNMR spectrogram;
FIG. 15 is a mass spectrum of the sulphone-piperazine-furanone derivative of Artemisia annua prepared in example 5 of the present invention;
FIG. 16 shows the preparation of sulphone-piperazine-furanone derivatives of Artemisia annua prepared in example 6 of the present invention1HNMR spectrogram;
FIG. 17 shows the preparation of sulphone-piperazine-furanone derivatives of Artemisia annua prepared in example 6 of the present invention13CNMR spectrogram;
FIG. 18 is a mass spectrum of the sulphone-piperazine-furanone derivative of Artemisia annua prepared in example 6 of the present invention.
Detailed Description
The present invention is described in terms of particular embodiments, other advantages and features of the invention will become apparent to those skilled in the art from the following disclosure, and it is to be understood that the described embodiments are merely exemplary of the invention and that it is not intended to limit the invention to the particular embodiments disclosed. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
The following examples used the following starting materials:
the sweet wormwood sulphone-piperazine is prepared by the following method:
adding 3.5g of anhydrous thiomorpholine and 35mL of dry dichloromethane into a 250mL three-neck flask, and stirring at room temperature until the anhydrous thiomorpholine and the dry dichloromethane are completely dissolved; adding DHA (2g, 7mmol) and 25mL of dry dichloromethane into a 200mL three-neck flask under the protection of Ar gas, stirring at room temperature for 5min, then adding 65 mu L of dry DMSO, continuing stirring for 2min, and then slowly dropwise adding 0.6-0.7mL of oxalyl chloride; slowly dripping the dichloromethane solution of thiomorpholine into the reaction solution, reacting at room temperature overnight, washing the reaction solution with 20mL saturated sodium carbonate and 20mL saturated sodium chloride after the reaction is finished, extracting the water phase with 3x 25mL ethyl acetate, combining the organic phases, and adding anhydrous Na2SO4Drying, vacuum filtering, removing solvent under reduced pressure, and separating with silica gel column chromatography to obtain artemisinin-thiomorpholine; a100 mL flask was charged with artemisinin-thiomorpholine (1.87g, 5.1mmol), 100mg sodium tungstate, 60mL of a mixture of tetrahydrofuran and water (V: 4:1), stirred at room temperature for 5min, and then 1.5mL hydrogen peroxide (33%) was added over 2h, followed by TLC, after disappearance of the starting material point, 100mL EA (ethyl acetate) was added to dilute the reaction, washed with 3X 30mL of saturated sodium chloride, and washed with anhydrous Na2SO4Drying the organic phase, performing suction filtration under reduced pressure, removing the solvent by rotary removal under reduced pressure, and performing silica gel column chromatography to obtain sweet wormwood sulfone; a100 mL flask was charged with 1, 6-hexanediol (2.36g, 20mmol), TBSCl (1.8g, 12mmol), anhydrous imidazole (2.1g, 30mmol) and 40mL of ultra-dry N, N-dimethylformamide, stirred at room temperature overnight, after completion of the reaction, the reaction was diluted with 40mL of water and 80mL of ethyl acetate, washed with 3X 35mL of saturated sodium chloride, and washed with anhydrous Na2SO4Drying the organic phase, vacuum filtering, removing solvent by rotary removal under reduced pressure, and separating with silica gel column chromatography to obtain extractMethyl tert-butylsiloxyhexanol; a100 mL flask was charged with dimethyl tert-butylsiloxanyl hexanol (1.6g, 6mmol), triphenyl phosphorus (1.83g, 7mmol), anhydrous imidazole (0.84g,12mmol) and 40mL dry THF, stirred at room temperature until the starting materials were completely dissolved, then elemental iodine (1.78g, 7mmol) was slowly added, the reaction was left to react overnight in the dark at room temperature, after completion of the reaction, the reaction mixture was diluted with 60mL ethyl acetate, washed with 25mL saturated sodium thiosulfate and then 2X 40mL saturated sodium chloride, and anhydrous Na2SO4Drying the organic phase, performing vacuum filtration, removing the solvent by rotary removal under reduced pressure, and performing silica gel column chromatography to obtain dimethyl tert-butyl siloxy iodohexane; adding dry diisopropylamine (0.63g, 6.3mmol), about 1mg of 2, 2-bipyridine and 10mL of dry THF into a 100mL two-necked flask at-30 ℃ in a stream of anhydrous Ar gas, stirring until completely dissolved, adding 4mL of n-butyllithium (1.6M, n-hexane solution), continuing to stir for 25-30min, then decreasing to-78 ℃, adding 10mL of dry tetrahydrofuran solution dissolved with artesunone (1.2g, 3mmol), continuing to stir for 45min, then adding 10mL of dry tetrahydrofuran solution dissolved with compound dimethyl tert-butyl silica iodohexane (1.19g), continuing to react for 3h, then gradually increasing to room temperature, after the reaction is finished, diluting the reaction solution with 80mL of ethyl acetate, washing with 40mL of saturated ammonium chloride, washing with 2X 40mL of saturated sodium chloride, washing with anhydrous Na2SO4Drying the organic phase, performing vacuum filtration, removing the solvent by rotary removal under reduced pressure, and performing silica gel column chromatography to obtain the artesunone derivative; dissolving 0.9g of sweet wormwood sulfone derivative and 1.42g of tetrabutylammonium fluoride in 40mL of THF (tetrahydrofuran) in a 50mL flask, reacting at room temperature overnight, adding 100mL of ethyl acetate to dilute the reaction after the reaction is finished, washing with 2x 40mL of saturated sodium chloride, and washing with anhydrous Na2SO4Drying the organic phase, carrying out suction filtration under reduced pressure, carrying out rotary removal on the solvent under reduced pressure to obtain a yellow oily substance, dissolving the oily substance by using 30mL of dry tetrahydrofuran, adding triphenylphosphine (0.4g, 1.52mmol) and anhydrous imidazole (0.21g, 3mmol), stirring at room temperature until the oily substance is completely dissolved, then adding elementary iodine (0.39g, 1.52mmol), stirring at room temperature in a dark place overnight, after the reaction is finished, diluting the reaction solution by using 60mL of ethyl acetate, washing by using 25mL of saturated sodium thiosulfate, washing by using 2x 25mL of saturated sodium chloride, and washing by using anhydrous Na2SO4Drying the organic phase, vacuum filtering, and rotary removing solvent under reduced pressureSeparating with silica gel column chromatography to obtain Artemisia apiacea sulfone iodide; adding 0.46g of sweet wormwood sulfone iodide, 0.43g of anhydrous piperazine and about 0.2mL of diisopropylethylamine into a flask, completely dissolving the mixture by using 20mL of dry tetrahydrofuran and 1mL of dry methanol under stirring at room temperature, gradually heating to 61 ℃, generating a white precipitate, reacting for 4 hours, washing the reaction solution by using a mixed solution of 15mL of saturated sodium carbonate and 20mL of saturated sodium chloride after the reaction is finished, extracting an aqueous phase by using 2x 25mL of ethyl acetate, combining organic phases, and adding anhydrous Na2SO4Drying the organic phase, performing suction filtration under reduced pressure, removing the solvent by rotary removal under reduced pressure, and performing silica gel column chromatography to obtain the sweet wormwood sulfone-piperazine.
Example 1
Sulfone-piperazine-furanone derivatives of Artemisia annua
The structural formula of the sweet wormwood sulfone-piperazine-furanone derivative is shown as a formula 1:
second, preparation method
The preparation method of the sweet wormwood sulfone-piperazine-furanone derivative comprises the following steps:
(a) dissolving sweet wormwood sulfone-piperazine and 3, 4-dichloro-5-methoxy furanone in acetonitrile to obtain a mixture, wherein the molar ratio of the sweet wormwood sulfone-piperazine to the halogenated furanone is 1: 1, and the concentration of the sweet wormwood sulfone-piperazine in the mixture is 0.012 mmol/mL;
(b) adding diisopropylethylamine into the mixture, and reacting under the stirring condition, wherein the molar ratio of the diisopropylethylamine to the sweet wormwood sulfone-piperazine is 3: 1, the reaction temperature is room temperature, and the reaction time is 4 hours;
(c) after the reaction is finished, evaporating to remove the solvent, and performing silica gel column chromatography separation and purification by using a mixture of petroleum ether and ethyl acetate with the volume ratio of 5: 1 as a developing agent to obtain the sweet wormwood sulfone-piperazine-furanone derivative.
Weighing the mass of the prepared sweet wormwood sulfone-piperazine-furanone derivative, and then dividing the weighed mass by the theoretical yield by 100 percent to obtain the yield of 85 percent by the preparation method.
Selecting the prepared sweet wormwood sulfone-piperazine-furanone derivatives to perform nuclear magnetic resonance and mass spectrometry respectively; wherein1H NMR spectrum,13The C NMR spectrum and the mass spectrum are shown in FIGS. 1-3;
as can be seen from fig. 1-3:1H NMR (CDCl3)δ5.68(s,1H),5.27(s,1H),4.18(d,J＝10.3Hz,1H),3.89(d,J＝2.4Hz,1H),3.82(d,J＝4.3Hz,2H),3.74–3.63(m,3H),3.43(q,J＝8.9,7.1Hz,2H),3.38–3.27(m,1H),3.06–2.96(m,1H),2.89(dd,J＝11.5,3.1Hz,1H),2.53(dt,J＝10.3,5.9Hz,2H),2.44(dt,J＝13.8,4.9Hz,1H),2.38–2.30(m,2H),2.00(dtd,J＝13.3,8.0,5.0Hz,2H),1.87(ddt,J＝13.6,6.7,3.5Hz,1H),1.71(ddt,J＝13.1,6.2,3.3Hz,2H),1.60–1.52(m,1H),1.51–1.42(m,5H),1.38(d,J＝4.6Hz,1H),1.32(d,J＝12.1Hz,10H),1.28–1.23(m,1H),1.22–1.16(m,1H),1.06–0.98(m,1H),0.94(d,J＝6.2Hz,3H),0.78(d,J＝7.1Hz,3H)。
13C NMR(CDCl3)δ167.9,162.5,161.7,153.6,132.5,127.8,126.5,123.1,104.0,97.2,91.7,90.9,86.4,80.0,60.4,58.2,58.1,54.4,53.8,53.4,53.3,52.7(x2),52.1(x2),51.6,51.3,47.3,46.0,45.5,41.7,41.2,37.3,36.0,34.0,29.1,28.9,26.8(x2),26.5,26.3,26.2,25.8,24.6,23.1,21.4,20.8,20.1,13.3,11.9。
HRMS m/z:calcd for C34H55ClN3O9S 716.3342,found 716.3342[M+H]+。
therefore, the prepared product can be determined to be the sweet wormwood sulphone-piperazine-furanone derivative shown in the formula 1.
Example 2
Sulfone-piperazine-furanone derivatives of Artemisia annua
The structural formula of the sweet wormwood sulfone-piperazine-furanone derivative is shown as a formula 2:
second, preparation method
The above-mentioned Artemisia apiacea sulfone-piperazine-furanone derivatives were prepared in the same manner as in example 1 except that 3, 4-dichloro-5-menthoxypuranone was used instead of 3, 4-dichloro-5-methoxyfuranone.
Weighing the mass of the prepared sweet wormwood sulfone-piperazine-furanone derivative, and then dividing the weighed mass by the theoretical yield by 100 percent to obtain the yield of 82 percent by the preparation method.
Selecting the prepared sweet wormwood sulfone-piperazine-furanone derivatives to perform nuclear magnetic resonance and mass spectrometry respectively; wherein1H NMR spectrum,13The C NMR spectrum and the mass spectrum are shown in FIGS. 4-6;
as can be seen from fig. 4-6:1H NMR(CDCl3)δ5.78(d,J＝15.7Hz,1H),5.27(s,1H),4.18(d,J＝10.2Hz,1H),3.74(dq,J＝10.5,5.0Hz,1H),3.61(dt,J＝14.6,5.7Hz,1H),3.57–3.49(m,1H),3.48–3.39(m,1H),3.39–3.23(m,1H),3.00(t,J＝12.6Hz,1H),2.89(dd,J＝11.2,3.1Hz,1H),2.74(s,1H),2.58–2.45(m,3H),2.32(ddd,J＝15.5,10.3,3.4Hz,3H),2.26–2.18(m,1H),2.14(qd,J＝6.9,2.4Hz,1H),2.06–1.96(m,2H),1.92–1.82(m,1H),1.68(ddp,J＝20.4,10.0,3.4Hz,4H),1.55(dt,J＝13.7,4.3Hz,1H),1.47(tt,J＝10.3,5.3Hz,5H),1.35–1.28(m,7H),1.28–1.15(m,9H),1.14–1.05(m,1H),1.04–0.97(m,1H),0.97–0.83(m,12H),0.82(s,1H),0.80–0.77(m,3H),0.74(dd,J＝7.0,4.9Hz,3H)。
13C NMR(CDCl3)δ168.1,154.8,132.2,104.0,102.1,97.0,91.2,90.9,87.1,84.3,80.7,80.0,77.2(x2),60.4,58.2,52.6,51.6,51.3,47.9,47.8,47.4,46.8(x2),45.5,42.3,42.0,40.2,37.3,36.0,34.0,33.8(x2),31.5,31.4,31.3,29.1(x2),28.9,26.8,26.5,26.3,25.8,25.7,25.2,24.9,24.6,23.2,22.5,22.1,21.9,21.8,21.4,21.0,20.7(x2),20.1,18.8,15.7,15.6,13.3。
HRMS m/z:calcd for C43H71ClN3O9S 840.4594,found 840.4594[M+H]+。
therefore, the prepared product can be determined to be the sweet wormwood sulphone-piperazine-furanone derivative shown in the formula 2.
Example 3
Sulfone-piperazine-furanone derivatives of Artemisia annua
The structural formula of the sweet wormwood sulfone-piperazine-furanone derivative is shown as a formula 3:
second, preparation method
The above-mentioned Artemisia apiacea sulfone-piperazine-furanone derivatives were prepared by the same method as in example 1, except that 3, 4-dichloro-5-borneoxy furanone was used instead of 3, 4-dichloro-5-methoxy furanone.
Weighing the mass of the prepared sweet wormwood sulfone-piperazine-furanone derivative, and then dividing the weighed mass by the theoretical yield by 100 percent to obtain the yield of 80 percent by the preparation method.
Selecting the prepared sweet wormwood sulfone-piperazine-furanone derivatives to perform nuclear magnetic resonance and mass spectrometry respectively; wherein1H NMR spectrum,13The C NMR spectrum and the mass spectrum are shown in FIGS. 7 to 9;
as can be seen from fig. 7-9:1H NMR(CDCl3)δ5.73(s,1H),5.27(s,1H),4.27(qd,J＝7.1,5.1Hz,1H),4.18(d,J＝10.3Hz,1H),3.83(dq,J＝9.3,7.1Hz,1H),3.77–3.70(m,3H),3.70–3.61(m,1H),3.44(h,J＝6.2,4.7Hz,3H),3.37–3.28(m,1H),3.05–2.94(m,1H),2.89(dd,J＝11.0,3.1Hz,1H),2.53(ddt,J＝17.1,6.5,3.2Hz,3H),2.43(dq,J＝14.4,5.0Hz,1H),2.38–2.27(m,3H),2.03–1.96(m,2H),1.92–1.83(m,1H),1.71(dtd,J＝9.5,6.4,5.8,3.4Hz,4H),1.56(dt,J＝13.8,4.3Hz,2H),1.47(dtd,J＝11.7,8.3,5.1Hz,4H),1.32(td,J＝7.1,4.7Hz,12H),1.26(q,J＝7.0Hz,3H),1.07–0.98(m,1H),0.95(d,J＝6.2Hz,3H),0.79(d,J＝7.1Hz,3H)。
13C NMR(CDCl3)δ168.5,163.1,161.6,156.4,152.2,150.2,135.9,104.0,97.5,91.8,90.9,80.0,77.2,72.6,63.7,62.8,62.7,60.2,58.2,58.1,52.8,52.7,52.1,51.6,51.3,47.4,46.0,45.5,41.3,37.3,36.0,34.0,29.1(x2),28.9,26.8(x2),26.8,26.5,26.4,26.3,25.8,24.6,23.1,21.4,20.1,14.8,13.9,13.8,13.3。
HRMS m/z:calcd for C43H69ClN3O9S 838.4438,found 838.4438[M+H]+。
therefore, the prepared product can be determined to be the sweet wormwood sulphone-piperazine-furanone derivative shown in the formula 3.
Example 4
Sulfone-piperazine-furanone derivatives of Artemisia annua
The structural formula of the sweet wormwood sulfone-piperazine-furanone derivative is shown as a formula 4:
second, preparation method
The above-mentioned Artemisia apiacea sulfone-piperazine-furanone derivative was prepared in the same manner as in example 1 except that 3, 4-dibromo-5-methoxyfuranone was used instead of 3, 4-dichloro-5-methoxyfuranone.
Weighing the mass of the prepared sweet wormwood sulfone-piperazine-furanone derivative, and then dividing the weighed mass by the theoretical yield by 100 percent to obtain the yield of 80 percent by the preparation method.
Selecting the prepared sweet wormwood sulfone-piperazine-furanone derivatives to perform nuclear magnetic resonance and mass spectrometry respectively; wherein1H NMR spectrum,13The C NMR spectrum and the mass spectrum are shown in FIGS. 10-12;
as can be seen from fig. 10-12:1H NMR(CDCl3)δ5.70(d,J＝10.0Hz,1H),5.28(s,1H),4.19(d,J＝10.3Hz,1H),3.69(d,J＝22.8Hz,3H),3.52–3.27(m,5H),2.90(d,J＝11.4Hz,1H),2.54(ddq,J＝15.9,10.7,5.8,5.1Hz,3H),2.44(dd,J＝9.5,4.8Hz,1H),2.39–2.28(m,3H),2.04–1.95(m,2H),1.95–1.82(m,1H),1.71(dq,J＝13.6,4.9,4.2Hz,2H),1.60(s,4H),1.47(d,J＝10.2Hz,3H),1.37(s,3H),1.33(d,J＝12.2Hz,4H),1.29–1.21(m,2H),1.08–0.99(m,1H),0.95(d,J＝6.2Hz,3H),0.91–0.82(m,8H),0.79(dd,J＝157.8,7.1Hz,3H)。
13C NMR(CDCl3)δ162.1,154.6,132.2,128.9,104.2,91.9,91.0,87.3,83.3,80.1,77.2,58.3,52.9,51.8,51.5,49.4,47.9,47.5,46.2,45.6,44.9(x2),41.5,37.4,36.2,34.2,29.3,29.0,27.0,26.6,26.5,25.9,24.8,23.3,21.6,20.2,19.6(x2),18.8,13.5。
HRMS m/z:calcd for C34H55BrN3O9S 760.2837,found 760.2837[M+H]+。
therefore, the prepared product can be determined to be the sweet wormwood sulphone-piperazine-furanone derivative shown in the formula 4.
Example 5
Sulfone-piperazine-furanone derivatives of Artemisia annua
The structural formula of the sweet wormwood sulfone-piperazine-furanone derivative is shown as a formula 5:
second, preparation method
The above-mentioned sweet wormwood sulfone-piperazine-furanone derivative was prepared in substantially the same manner as in example 1, except that 3, 4-dibromo-5-menthyloxyfuranone was used instead of 3, 4-dichloro-5-methoxyfuranone.
Weighing the mass of the prepared sweet wormwood sulfone-piperazine-furanone derivative, and dividing the weighed mass by the theoretical yield by 100 percent to obtain the yield of 78 percent by the preparation method.
Selecting the prepared sweet wormwood sulfone-piperazine-furanone derivatives to perform nuclear magnetic resonance and mass spectrometry respectively; wherein1H NMR spectrum,13The C NMR spectrum and the mass spectrum are shown in FIGS. 13 to 15;
as can be seen from fig. 13-15:1H NMR(CDCl3)δ5.79(s,1H),5.28(s,1H),4.19(d,J＝10.2Hz,1H),3.83–3.71(m,1H),3.69–3.59(m,1H),3.54(td,J＝10.6,4.4Hz,1H),3.47–3.27(m,4H),2.90(d,J＝11.5Hz,1H),2.53(ddt,J＝21.4,6.8,3.9Hz,3H),2.43–2.28(m,3H),2.26–2.14(m,1H),2.00(dt,J＝14.5,4.4Hz,3H),1.89(dddd,J＝13.3,9.8,5.9,3.5Hz,1H),1.70(dddd,J＝21.2,13.4,7.1,3.4Hz,4H),1.56(dt,J＝13.7,4.2Hz,1H),1.46(q,J＝7.1,5.6Hz,4H),1.36–1.29(m,3H),1.25(t,J＝7.1Hz,2H),1.21–1.10(m,1H),1.07–0.99(m,1H),0.95(d,J＝6.2Hz,3H),0.93–0.89(m,9H),0.88–0.82(m,1H),0.79(d,J＝7.1Hz,3H),0.75(dd,J＝6.9,4.4Hz,3H)。
13C NMR(CDCl3)δ168.6,163.0,161.1,157.4,135.7,104.0,98.0,91.8,90.9,80.6,80.0,77.3,77.2,73.6,60.4,58.2,52.7,51.6,51.4,48.0,47.6,46.9,46.0 45.5,42.4,40.2,37.3,36.1,34.1,33.8,31.5,31.3,29.2,28.9,26.9,26.5,26.4,25.8,25.7,24.9,24.7,23.2,22.6,22.1,21.9,21.5,21.1,20.7,20.1,19.2,15.9,15.7,13.4。
HRMS m/z:calcd for C43H71BrN3O9S 884.4089,found 884.4089[M+H]+。
therefore, the prepared product can be determined to be the sweet wormwood sulphone-piperazine-furanone derivative shown in the formula 5.
Example 6
Sulfone-piperazine-furanone derivatives of Artemisia annua
The structural formula of the sweet wormwood sulfone-piperazine-furanone derivative is shown as the formula 6:
second, preparation method
The above-mentioned Artemisia apiacea sulfone-piperazine-furanone derivative was prepared in the same manner as in example 1 except that 3, 4-dibromo-5-bornyloxyfuranone was used instead of 3, 4-dichloro-5-methoxyfuranone.
Weighing the mass of the prepared sweet wormwood sulfone-piperazine-furanone derivative, and then dividing the weighed mass by the theoretical yield by 100 percent to obtain the yield of 81 percent by the preparation method.
Selecting the prepared sweet wormwood sulfone-piperazine-furanone derivatives to perform nuclear magnetic resonance and mass spectrometry respectively; wherein1H NMR spectrum,13The C NMR spectrum and the mass spectrum are shown in FIGS. 16 to 18;
as can be seen from FIGS. 16-18:1H NMR(CDCl3)δ5.72(d,J＝10.2Hz,1H),5.28(s,1H),4.18(d,J＝10.3Hz,1H),3.75(d,J＝5.0Hz,2H),3.68–3.61(m,1H),3.52–3.28(m,5H),3.12–2.95(m,2H),2.93–2.87(m,1H),2.52(tq,J＝10.6,5.9,5.5Hz,3H),2.42(q,J＝5.7Hz,1H),2.39–2.28(m,3H),2.00(dt,J＝14.7,4.4Hz,2H),1.88(ddt,J＝11.1,9.6,3.2Hz,1H),1.77–1.63(m,5H),1.53(s,2H),1.46(q,J＝7.1,5.2Hz,4H),1.36–1.30(m,9H),1.29–1.21(m,2H),1.10–0.99(m,6H),0.95(d,J＝6.2Hz,3H),0.90–0.83(m,8H),0.79(d,J＝7.1Hz,3H)。
13C NMR(CDCl3)δ168.6,163.0,161.8,157.0,151.6,135.9,118.7,104.0,99.1,91.8,90.9,87.0,83.2,83.1,80.0(x2),77.2,73.1,60.4,58.3,58.2,53.1,52.8,52.2,51.6,51.4,49.3,49.0,47.8,47.6,47.4,46.0,45.5,44.8,44.6(x2),41.4,37.3,37.1,36.3,36.1,34.1,29.2,28.9,27.9,27.8(x2),27.0,26.9,26.8,26.5(x2),26.4(x2),25.8,24.7,23.2(x2),21.5,20.2,20.1,19.5(x2),18.7(x2),18.6,14.0,13.4(x2),13.33。
HRMS m/z:calcd for C43H69BrN3O9S 882.3932,found 882.3932[M+H]+。
therefore, the prepared product can be determined to be the sweet wormwood sulphone-piperazine-furanone derivative shown in the formula 6.
Experimental example 1
The experimental example is an in vitro inhibitory activity study of the sweet wormwood herb sulfone-piperazine-furanone derivatives, Vincristine (VCR), cytarabine (ARA) and Dihydroartemisinin (DHA) prepared in examples 1 to 6 on hepatoma cell SMMC-7721 and hepatic normal cell LO2 respectively;
the experimental method comprises the following steps:
taking the cell to be tested with good growth state in logarithmic growth phase, adjusting the density to 5 × 10 with 1640 complete culture medium4one/mL, the suspension was inoculated into a 96-well plate at 100. mu.L per well, divided into 6 plates, and cultured overnight at 37 ℃ (100. mu.L of sterile PBS was added to the wells around the cell wells);
after the cells grow well adherent to the wall for 24h, absorbing old culture solution, adding 10 μ L of different concentrations of the compounds to be tested into each culture well, wherein the concentrations are respectively 10, 25, 50, 100 and 200 μ g/mL, each concentration is provided with 3 parallel repeat wells, and an equal volume of dimethyl sulfoxide (DMSO) solvent is simultaneously arrangedAnd drug-free medium in blank control wells at 37 ℃ with 5% CO2Continuously culturing in the incubator;
after culturing the substance to be tested for 24 hours, the supernatant was discarded, and the morphology of the cells was observed using an inverted microscope, and a photograph was taken. Then, 10. mu.L (2mg/mL in PBS) of MTT was added to each well, after further culturing for 4 hours, the culture supernatant in each well was aspirated, 150. mu.L of dimethyl sulfoxide was added to each well, and after shaking for 10min to dissolve the bluish-purple crystals sufficiently, the absorbance (A) of each well sample was measured at 568nm with a microplate reader, and the average value was taken.
The results of the experiment are shown in table 1:
TABLE 1
μM＝μmol/mL
As can be seen from Table 1:
examples 1 and 3 have higher in vitro inhibitory effect on liver cancer cells SMMC-7721, which exceeds first-line antitumor drugs of vincristine and cytarabine; the compound obtained in example 1 has higher in vitro inhibition effect on liver cancer SMMC-7721 cells than vincristine and cytarabine, and has very low toxicity on liver normal LO2 cells. Example 1 was the least cytotoxic to normal liver LO2, lower than vincristine and cytarabine.
Experimental example 2
The experimental example is an in vitro inhibition activity study of the sweet wormwood herb sulfone-piperazine-furanone derivatives prepared in example 1 on liver cancer cells SMMC-7721, MHCC97H, colon cancer cells HCT116 and normal colon cells CCD18CO, breast cancer cells MCF-7 and normal breast cancer cells MCF-10A, prostate cancer cells DU145 and normal prostate cells RWPE-1 for 48 hours respectively;
the experimental method comprises the following steps: the detection method in example 1 was the same except that the concentrations were 0.01, 0.1, 1, 10, and 25. mu.g/mL instead of 10, 25, 50, 100, and 200. mu.g/mL, respectively.
The results of the experiment are shown in table 2:
TABLE 2
μM＝μmol/mL
As can be seen from Table 2:
the compound obtained in example 1 has good in-vitro inhibition effect on liver cancer cells SMMC-7721, MHCC97H, colon cancer cells HCT116, breast cancer cells MCF-7 and prostate cancer cells DU145 within 48h, and has low toxicity on liver normal cells LO2, colon normal cells CCD18CO, breast normal cells MCF-10A and prostate normal cells RWPE-1 within 48 h.
Experimental example 3
This example is conducted using different concentrations of the sulphone-piperazine-furanone derivatives of Artemisia annua prepared in example 1 in 100. mu. mol/L FeSO4Research on in-vitro inhibitory activity of the cultured liver cancer cells SMMC-7721 and MHCC 97H;
the experimental method comprises the following steps:
taking the cell to be tested with good growth state in logarithmic growth phase, adjusting the density to 5 × 10 with 1640 complete culture medium4one/mL, the suspension was inoculated into a 96-well plate at 100. mu.L per well, divided into 6 plates, and cultured overnight at 37 ℃ (100. mu.L of sterile PBS was added to the wells around the cell wells).
After the adherent growth of the cells is good for 12 hours, absorbing the old culture solution, and replacing the culture medium containing 100 mu mol/L ferrous sulfate to culture for 12 hours at 37 ℃; discarding the culture medium, adding 10 μ L of test substance compound with different concentrations into each culture well, the concentration is 0.01, 0.1, 1, 10, 25 μ g/mL, each concentration is provided with 3 parallel repeat wells, and blank control wells containing equal volume of dimethyl sulfoxide (DMSO) solvent and no drug culture medium are provided at 37 deg.C and 5% CO2The cultivation is continued in the incubator.
Culturing the substance to be detected for 48h, removing the supernatant, observing the cell morphology by using an inverted microscope, and taking a picture; then, 10. mu.L (2mg/mL in PBS) of MTT was added to each well, after further culturing for 4 hours, the culture supernatant in each well was aspirated, 150. mu.L of dimethyl sulfoxide was added to each well, and after shaking for 10min to dissolve the bluish-purple crystals sufficiently, the absorbance (A) of each well sample was measured at 568nm with a microplate reader, and the average value was taken.
The results of the experiment are shown in table 3:
TABLE 3
Reactiona:Culture cells with 100μmol/L FeSO4
As can be seen from Table 3:
simulating in vivo environment when liver cancer cells are facing Fe2+When the compound is over-expressed, the compound in the example 1 has an enhanced in vitro inhibition effect on liver cancer cells SMMC-7721 and MHCC 97H.
Although the invention has been described in detail above with reference to a general description and specific examples, it will be apparent to one skilled in the art that modifications or improvements may be made thereto based on the invention. Accordingly, such modifications and improvements are intended to be within the scope of the invention as claimed.
Claims (9)
1. The sweet wormwood sulfone-piperazine-furan ether derivative is characterized by having the following structural formula:
2. the process for the preparation of the derivative of claim 1, comprising the steps of:
(a) dissolving sweet wormwood sulfone-piperazine and halogenated furanone in acetonitrile to obtain a mixture;
(b) adding diisopropylethylamine into the mixture, and reacting under the condition of stirring;
(c) and (3) after the reaction is finished, evaporating the solvent, separating and purifying to obtain the derivative.
3. The preparation method of claim 2, wherein the molar ratio of the sweet wormwood sulfone-piperazine to the halogenated furanone is 1: 0.8-1.2.
4. The preparation method according to claim 2, wherein the molar ratio of diisopropylethylamine to artesunone-piperazine is (2.8-3.2) to 1.
5. The method according to claim 2, wherein the reaction temperature is room temperature and the reaction time is 2 to 4 hours.
6. The method according to claim 2, wherein the halogenated furanone is selected from any one of 3, 4-dichloro-5-methoxyfuranone and 3, 4-dichloro-5-bornyloxyfuranone.
7. The preparation method according to claim 2, wherein the separation and purification mode is silica gel column chromatography, and the developing agent adopted by the silica gel column chromatography is a mixture of petroleum ether and ethyl acetate, wherein the volume ratio of the petroleum ether to the ethyl acetate is (2-20) to 1.
8. Use of the derivative according to claim 1 or the derivative obtained by the preparation method according to any one of claims 2 to 7 for preparing an antitumor drug.
9. An anti-hepatoma pharmaceutical formulation comprising a therapeutically effective amount of the derivative of claim 1 or the derivative prepared by the process of any one of claims 2 to 7.
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