CN111087301B - Synthesis method of ibuprofen caffeate and application of ibuprofen caffeate in preparation of immunosuppressive drugs - Google Patents

Synthesis method of ibuprofen caffeate and application of ibuprofen caffeate in preparation of immunosuppressive drugs Download PDF

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CN111087301B
CN111087301B CN201911336463.4A CN201911336463A CN111087301B CN 111087301 B CN111087301 B CN 111087301B CN 201911336463 A CN201911336463 A CN 201911336463A CN 111087301 B CN111087301 B CN 111087301B
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ibuprofen
caffeate
anhydrous dichloromethane
caffeic acid
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朱鑫
陈坤
武香香
曾华辉
闫敏
张岚
田启康
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Henan University of Traditional Chinese Medicine HUTCM
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Abstract

The invention discloses a synthesis method of ibuprofen caffeic acid ester and application thereof in preparing immunosuppressive drugs, wherein ibuprofen, anhydrous dichloromethane and pyridine are slowly dripped into SOCl under room-temperature stirring2CH (1)2Cl2Refluxing the solution at 55-65 deg.C for 2 hr, spin drying, and adding anhydrous dichloromethane to obtain CH of ibuprofen acyl chloride2Cl2A solution; cooling caffeic acid, DMF and anhydrous dichloromethane in ice water bath to 5 ℃, dropwise adding triethylamine, and slowly dropwise adding CH of ibuprofen acyl chloride under stirring2Cl2Stirring the solution in an ice water bath for 2 hours, and tracking and detecting the reaction by TLC to obtain the ibuprofen caffeic acid ester. The ibuprofen Caffeate (CI) provided by the invention is used for detecting the cytotoxicity of ibuprofen caffeate by an MTT method, and the result shows that CI has very remarkable inhibition on MCF-7 cell proliferation and HepG2 cell proliferation; CI solutions with different concentrations have the functions of inducing apoptosis and inhibiting proliferation of breast cancer cells.

Description

Synthesis method of ibuprofen caffeate and application of ibuprofen caffeate in preparation of immunosuppressive drugs
Technical Field
The invention belongs to the technical field of organic synthesis, and particularly relates to a synthesis method of ibuprofen caffeate and application of the ibuprofen caffeate in preparation of immunosuppressive drugs.
Background
Since the structure of salicylic acid is found in willow bark, the clinical application of non-steroidal anti-inflammatory drugs (NSAIDs) including aspirin and ibuprofen has been known for many years. Their main mode of action is that inhibition of cyclooxygenase enzymes (i.e. COX-1 and COX-2) results in a reduction in the synthesis of prostaglandins (messenger molecules in the inflammatory process) and thus achieves analgesic anti-inflammatory effects. Ibuprofen has been used clinically for many years, belongs to the most widely applicable non-steroidal drugs, and can be applied to the treatment of general antipyretic analgesia, rheumatic arthritis and neuritis.
There are a number of reports focusing on the study of non-steroidal anti-inflammatory drugs on tumors. Studies show that the risk of malignant tumors such as prostate cancer, colon cancer, bladder cancer, liver cancer, pancreatic cancer and the like can be reduced by taking ibuprofen for a long time. Experiments show that certain non-steroidal drugs have the potential to inhibit the proliferation and induce apoptosis of ovarian cancer cells. It has been found that a secondary subtype of cyclooxygenase (COX-2) plays an important role in the progression and development of tumors. However, the anti-tumor mechanism of ibuprofen has not been elucidated. The research aims to discuss the effect of the structurally modified ibuprofen on liver cancer cells HepG2 and breast cancer cells MCF-7, and lays a theoretical foundation for clinically further treating breast cancer by combined application of ibuprofen.
Disclosure of Invention
In view of the problems in the prior art, the present invention provides a composition of which inflammation is an important component of tumor progression, and non-steroidal anti-inflammatory drugs (NSAIDs) are effective in inhibiting early tumor progression and malignant transformation. For example, ibuprofen is effective in reducing the risk of various human cancers, including breast, lung and prostate cancers. NSAIDs have been reported to inhibit cancer by a Cyclooxygenase (COX) mechanism, however there are also COX independent targets including peroxisome proliferator activated receptors, lipoxygenase and apoptotic signals. The toxicity of conventional NSAIDs is related, which makes their long-term use in the prevention of cancer problematic.
The present invention provides a novel chemical modification of conventional NSAIDs to reduce their toxicity and enhance their efficacy. The modified ibuprofen Caffeate (CI) is a derivative of ibuprofen by combining traditional Chinese medicine phenolic acid active ingredients. The method aims to research the proliferation and apoptosis conditions of 2 tumor cell strains after the ibuprofen derivative acts on MCF-7 cells and HepG2 cells in vitro, and provides a new idea for clinical tumor treatment. The invention firstly uses an MTT method to detect the proliferation inhibition condition of 2 tumor cell strains under the action of ibuprofen and CI with different concentrations. Experimental results show that CI has good effect on 2 kinds of tumor cells. Flow cytometry analysis found that dosing at different concentrations after CI action increased the apoptosis rate of MCF-7 cell lines and affected cell cycle progression. CI has some anti-tumor effect, and its molecular mechanism is to be further explored.
In order to solve the technical problems, the invention adopts the following technical scheme:
a synthesis method of ibuprofen caffeate comprises the following steps:
(1) adding ibuprofen, anhydrous dichloromethane and pyridine into a three-necked bottle in sequence, and slowly dropwise adding SOCl while stirring at room temperature2CH (A) of2Cl2The solution was refluxed at 55-65 ℃ for 2 hours while maintaining the oil bath temperature, after which the reaction was slowly cooled and the excess SOCl was removed under reduced pressure2Spin-drying to give a pale yellow solid, and adding anhydrous dichloromethane to give ibuprofen acid chloride CH2Cl2Sealing the solution for later use; the methanol-derived ester method checks whether the acid chloride is successfully prepared. Taking a little methanol into a clean EP tube with the volume of 1.5mL, dropwise adding a trace amount of ibuprofen acyl chloride, uniformly mixing, and performing TLC (thin layer chromatography) plate counting to confirm that the preparation of the acyl chloride is successful;
(2) adding caffeic acid, DMF and anhydrous dichloromethane into another three-necked bottle, cooling to 5 ℃ in ice water bath, dropwise adding triethylamine, and slowly dropwise adding CH of ibuprofen acyl chloride obtained in the step (1) under stirring2Cl2Continuously stirring the solution at low temperature for 2h, performing TLC tracking detection reaction, performing suction filtration, drying the filtrate to obtain an oily substance, performing silica gel column chromatography to obtain ibuprofen caffeic acid ester white solid, wherein the reaction route is as follows:
Figure BDA0002331050110000031
further, in the step (1), 20mL of anhydrous dichloromethane is required for 15mmol of ibuprofen, and 1 drop of pyridine is required for 10mmol of ibuprofen.
Further, in the step (1), SOCl is required for 15mmol ibuprofen2CH (A) of2Cl25mL of solution in which SOCl is present2It was 0.5 mL.
Further, the molar ratio of ibuprofen to caffeic acid is 5: 1.
Further, the molar ratio of caffeic acid to triethylamine in the step (2) is 3: 5.
Further, the volume ratio of DMF to anhydrous dichloromethane in the step (2) is 1:10, and 10mL of anhydrous dichloromethane is needed for 3mmol of caffeic acid.
Further, the eluent used for silica gel column chromatography in the step (2) is petroleum ether: ethyl acetate (V: V) ═ 5: 1.
The ibuprofen caffeate prepared by the synthesis method is applied to preparation of immunosuppressive drugs.
The invention has the beneficial effects that: the compound ibuprofen caffeic acid ester provided by the invention is prepared by an acyl chloride method; dissolving a single-solvent insoluble raw material caffeic acid by adopting a mixed solvent; the method is simple and convenient for industrial transformation. The compound ibuprofen caffeate provided by the invention is used for detecting the cytotoxicity of the ibuprofen caffeate through an MTT method, and the result shows that the inhibition of the ibuprofen Caffeate (CI) on MCF-7 cell proliferation and HepG2 cell proliferation is very obvious; the effect of CI on MCF-7 cell apoptosis is further tested, the proportion of apoptotic cells in the cells is continuously increased along with the increase of CI concentration, and CI solutions with different concentrations have the effects of inducing apoptosis and inhibiting proliferation of breast cancer cells, and the growth inhibition rate of the CI solutions has concentration dependence.
Drawings
FIG. 1 shows the inhibition of MCF-7 cell proliferation by different concentrations of ibuprofen and CI.
FIG. 2 shows the inhibition of HepG2 cell proliferation by different concentrations of ibuprofen and CI.
FIG. 3 shows the results of flow cytometry to determine the effect of CI on MCF-7 apoptosis.
FIG. 4 is a hydrogen spectrum of CI.
FIG. 5 is a carbon spectrum of CI.
FIG. 6 is a mass spectrum of CI.
Detailed Description
The present invention will be further described with reference to the following examples. It is to be understood that the following examples are illustrative only and are not intended to limit the scope of the invention, which is to be given numerous insubstantial modifications and adaptations by those skilled in the art based on the teachings set forth above.
Example 1
The synthesis of ibuprofen caffeate in this example was as follows:
(1) to a three-necked flask were added 3.09g (15mmol) of ibuprofen, 20mL of anhydrous dichloromethane, and 1 drop of pyridine in this order. Slowly dropwise adding SOCl at room temperature while stirring2(0.5mL) of CH2Cl25mL of the solution. The oil bath temperature was maintained at 60 deg.C for 2 hours at reflux. The reaction was then slowly cooled and excess SOCl removed under reduced pressure2Spin-drying to obtain a light yellow solid, adding 5mL of anhydrous dichloromethane, and sealing for later use;
the methanol-derived ester method checks whether the acid chloride is successfully prepared. Taking a little methanol into a clean EP tube with the volume of 1.5mL, dropwise adding a trace amount of ibuprofen acyl chloride, uniformly mixing, and performing TLC (thin layer chromatography) plate counting to confirm that the preparation of the acyl chloride is successful;
(2) adding 0.54g (3mmol) of caffeic acid, 1mL of DMF and 10mL of anhydrous dichloromethane into another three-necked flask, cooling to about 5 ℃ in an ice water bath, dropwise adding 5mmol of triethylamine, and slowly dropwise adding CH of ibuprofen acyl chloride in the previous step while stirring2Cl2And (3) solution. The reaction was stirred continuously at low temperature for 2 h. The reaction was monitored by TLC. Filtering, and spin-drying the filtrate to obtain oily substance. Silica gel column chromatography (petroleum ether: ethyl acetate ═ 5:1) afforded 427mg of ibuprofen Caffeate (CI) as a white solid.
CI structure
Figure BDA0002331050110000051
Ibuprofen caffeate, white solid, yield 79.1%, mp: 121.8-122.5 ℃. Molecular formula C22H24O5And M is 368. Wherein MS (ESI, m/z): [ M-H ]]+ 367;1H NMR(500MHz，DMSO-d6)，δ/×10-6：0.83(s，3H，CH3)，0.84(s，3H，CH3)，1.78～1.82(m，1H，CH)，1.40(d，3H，CH-CH3)，2.43(d，2H，CH-CH2)，3.72(m,1H，CH-CH3)，6.53(d，1H，J＝16Hz，CH＝CH)，7.52(d，1H，J＝16Hz，CH＝CH)，7.15(d，2H，J＝7.95Hz)，7.23(d，2H，J＝7.9Hz)，7.13(d，1H，J＝8.55Hz)，7.16～7.19(dd，1H，J＝2.9、7.8Hz)，7.57(d，1H)。13C NMR(500MHz，DMSO-d6)，δ/×10-6：171.64，167.25，143.14，142.22，141.96，140.17，137.00，133.20，129.29，127.23，126.71，123.76，122.86，120.43，44.18，43.79，29.52，22.10，18.64，18.38。
first, Effect of synthetic Compounds on cancer cell proliferation
1. Cell culture
Human liver cancer cell HepG2 and breast cancer cell MCF-7 in DMEM complete medium (DMEM + 10% fetal bovine serum + 1% double antibody) at 37 deg.C and 5% CO2And culturing in a saturated humidity incubator. When 80-85% of the cells adhered to the culture dish are observed under a microscope, the cells are digested and passaged by 1mL of 0.25% pancreatin.
2. MTT method for detecting inhibition rate
After 3-4 generations of cells, laying a 96-well plate with 5000-10000 cells/well, observing, and then putting into an incubator for culturing for 24 h. When the cell density is observed to reach 85% under the microscope, CI with different concentrations (50, 100, 150, 200, 250, 300, 350, 400 mu mol/L) is added, a normal group and a blank group are arranged, 6 multiple holes are arranged, and the mixture is put into an incubator to be cultured for 24 hours. After 24h, 20. mu.l of MTT (5mg/ml) was added to each well and incubation was continued at 37 ℃ and the culture was terminated after 4 h. Carefully removing the supernatant of the culture medium, adding 150. mu.l DMSO into each well, incubating at 37 ℃ for 10min, shaking the wells on a flat shaker at a low speed for 10min to fully dissolve the crystals, adjusting to zero with a blank control, measuring the absorbance of each well at 490nm, averaging, and calculating the inhibition rate and IC 50. The results are shown in FIGS. 1 and 2.
As can be seen from the results in FIGS. 1 and 2, CI has stronger inhibiting effect on MCF-7 cells and HepG2 cells in the range of 50-400 mu mol/L and shows better activity, and the IC 50 value of CI acting on MCF-7 in 24 hours is 273.6 mu mol/L and the IC 50 value of CI acting on HepG2 is 223.3 mu mol/L through calculation of Graph Pad Prism software.
3. Flow cytometry detection of breast cancer cell apoptosis rate
At 2X 105The cells were plated on 6-well plates, cultured for 24 hours, and then the supernatant was discarded, and fresh culture medium containing CI at concentrations of 200. mu. mol/L, 273.7. mu. mol/L, and 300. mu. mol/L was added to the plates, and a control group was set. After further culturing for 24h, 5X 10 cells were collected by centrifugation at each concentration of drug added5And (4) cells. The 5 Xbinding buffer was diluted with double distilled water to 1 Xworking solution, 500. mu.L of 1 Xbinding buffer was taken to resuspend the cells, and 5. mu.L of Annexin V-CITC and 10. mu.L of PI were added to each tube. After gentle vortex mixing, incubate for 5 min at room temperature in the dark. Annexin V-CITC (Ex 488 nm; Em 530nm) was detected by a CITC detection channel and PI was detected by a PE detection channel on a flow cytometer. The results are shown in FIG. 3.
As can be seen from FIG. 3, the control group contained only 0.19% of all the cells, while the CI concentration increased, the proportion of the apoptotic cells increased, and the MCF-7 treated with 350. mu. mol/L CI had a high proportion of apoptosis of 82.17%. It is observed that CI solutions with different concentrations have the effects of inducing apoptosis and inhibiting proliferation of breast cancer cells, and the growth inhibition rate of the breast cancer cells has concentration dependence.
The foregoing shows and describes the general principles and features of the present invention, together with the advantages thereof. It will be understood by those skilled in the art that the present invention is not limited to the embodiments described above, which are described in the specification and illustrated only to illustrate the principle of the present invention, but that various changes and modifications may be made therein without departing from the spirit and scope of the present invention, which fall within the scope of the invention as claimed. The scope of the invention is defined by the appended claims and equivalents thereof.

Claims (8)

1. The synthesis method of ibuprofen caffeate is characterized by comprising the following steps of:
(1) adding ibuprofen, anhydrous dichloromethane and pyridine into a three-necked bottle in sequence, and slowly dropwise adding SOCl while stirring at room temperature2CH (A) of2Cl2The solution and the oil bath temperature are kept at 55-65 ℃ for refluxing for 2 hours,the reaction was then slowly cooled and excess SOCl removed under reduced pressure2，Spin-drying to give a pale yellow solid, and adding anhydrous dichloromethane to give ibuprofen acid chloride CH2Cl2Sealing the solution for later use;
(2) adding caffeic acid, DMF and anhydrous dichloromethane into another three-necked bottle, cooling to 5 ℃ in ice water bath, dropwise adding triethylamine, and slowly dropwise adding CH of ibuprofen acyl chloride obtained in the step (1) under stirring2Cl2Continuously stirring the solution in an ice water bath for 2 hours, carrying out TLC tracking detection reaction, carrying out suction filtration, carrying out spin drying on the filtrate to obtain an oily substance, and carrying out silica gel column chromatography to obtain ibuprofen caffeic acid ester white solid.
2. The method for synthesizing ibuprofen caffeate according to claim 1, wherein: in the step (1), 20mL of anhydrous dichloromethane is required for 15mmol of ibuprofen, and 1 drop of pyridine is required for 10mmol of ibuprofen.
3. The method for synthesizing ibuprofen caffeate according to claim 1, wherein: in the step (1), the 15mmol ibuprofen needs SOCl2CH (A) of2Cl25mL of solution in which SOCl is present2It was 0.5 mL.
4. The method for synthesizing ibuprofen caffeate according to claim 1, wherein: the molar ratio of ibuprofen to caffeic acid is 5: 1.
5. The method for synthesizing ibuprofen caffeate according to claim 1, wherein: the molar ratio of caffeic acid to triethylamine in the step (2) is 3: 5.
6. The method for synthesizing ibuprofen caffeate according to claim 1, wherein: the volume ratio of DMF to anhydrous dichloromethane in the step (2) is 1:10, and 10mL of anhydrous dichloromethane is needed for 3mmol of caffeic acid.
7. The method for synthesizing ibuprofen caffeate according to claim 1, wherein: the eluent used for silica gel column chromatography in the step (2) is petroleum ether and ethyl acetate V: V =5: 1.
8. Use of ibuprofen caffeate prepared by the synthesis method of any one of claims 1-7 in preparation of drugs for treating liver cancer and breast cancer.
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EP1339665A1 (en) * 2000-10-12 2003-09-03 Nicox S.A. Nitroderivatives as drugs for diseases having an inflammatory basis

Patent Citations (3)

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Publication number Priority date Publication date Assignee Title
US6110955A (en) * 1997-03-11 2000-08-29 Beacon Laboratories, Inc. Metabolically stabilized oxyalkylene esters and uses thereof
CN1354740A (en) * 1999-04-13 2002-06-19 尼科克斯公司 Pharmaceutical compounds
EP1339665A1 (en) * 2000-10-12 2003-09-03 Nicox S.A. Nitroderivatives as drugs for diseases having an inflammatory basis

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Title
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苯丙烯酸类衍生物和类似物的合成及其抗炎和抗癌活性研究(英文);张琳萍等;《药学学报》;19921231;第27卷(第11期);第817-823页 *

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