CN114751910B - Compound capable of inducing cell megalophage death and preparation method and application thereof - Google Patents
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Abstract
The invention discloses a compound capable of inducing apoptosis of macrovacuoles as well as a preparation method and application thereof, wherein the compound is 2-chloro-N- (4- (pyrazole [1,5-a ] pyrimidine-6-yl) phenyl) acetamide. The 2-chloro-N- (4- (pyrazole [1,5-a ] pyrimidine-6-yl) phenyl) acetamide of the invention has the effect of inducing tumor cell death, and the cell death is caused by the formation of a plurality of huge vacuoles in cells induced by the compound and is called macrovesicular death. The compound has higher clinical application value and good development prospect, and can be used for treating tumor diseases. The preparation method is simple and convenient and is suitable for synthesizing the compound in large quantity.
Description
Technical Field
The invention belongs to the technical field of medicinal chemistry, and particularly relates to a compound capable of inducing apoptosis of macrovacuoles as well as a preparation method and application thereof.
Background
Malignant tumor is a major disease seriously threatening human life and health, at present, most chemotherapy drugs in clinic kill tumor cells through an apoptosis mechanism to achieve a treatment effect, but due to tumor heterogeneity and the continuous evolution of the tumor cells under drug treatment, the chemotherapy drugs are continuously adapted to the external environment and gradually generate drug resistance to the chemotherapy drugs, so that the clinical application of the chemotherapy drugs in tumor treatment is restricted. Megaloblastic death (methusas) is a new form of non-apoptotic cell death discovered in recent years and is primarily characterized by the accumulation of numerous clear vacuoles in the cytoplasm, but does not have the general characteristics of apoptosis. Therefore, the development of the antineoplastic drug for inducing the apoptosis of the giant cell has important scientific significance and clinical value for improving the chemotherapy effect of malignant tumor.
Disclosure of Invention
Aiming at the prior art, the invention provides a compound capable of inducing cell megacyst type death, a preparation method and application thereof, aiming at solving the problem of drug resistance caused by chemotherapy drugs for killing tumor cells by the existing apoptosis mechanism.
In order to achieve the purpose, the invention adopts the technical scheme that: provides a compound capable of inducing apoptosis of cellular megaloplasma, which is 2-chloro-N- (4- (pyrazolo [1,5-a ] pyrimidin-6-yl) phenyl) acetamide and has a chemical formula
The invention also provides a preparation method of the compound capable of inducing apoptosis of the macrovacuoles, which comprises the following steps:
(1) Sequentially adding 2-bromomalonaldehyde and 5-aminopyrazole into ethanol in an ice water bath, stirring for reacting for 4-6 min, then dropwise adding concentrated hydrochloric acid, reacting for 5-7 h at room temperature, filtering, washing a filter cake, and drying to obtain a light brown solid;
(2) Mixing the light brown solid obtained in the step (1), 4-aminobenzene boronic acid pinacol ester, tetrakis (triphenylphosphine) palladium and potassium carbonate, adding dioxane/water mixed solution, reacting for 7-9 h at 70-90 ℃ under the protection of inert gas, evaporating to remove the solvent, extracting, washing and drying the residue, and purifying to obtain a yellow brown solid;
(3) And (3) dissolving the yellowish-brown solid obtained in the step (2) in dichloromethane, adding N, N-diisopropylethylamine, cooling in an ice water bath for 8-12 min, dropwise adding chloroacetyl chloride, reacting at room temperature for 1.5-2.5 h under the protection of inert gas, and extracting, washing, drying and purifying to obtain the yellow brown liquid.
On the basis of the technical scheme, the invention can be further improved as follows.
Further, the light brown solid has the formula
The yellow-brown solid has the formula
Furthermore, the dosage ratio of the 2-bromomalondialdehyde, the 5-aminopyrazole, the ethanol and the concentrated hydrochloric acid is 30mol; the dosage ratio of the light brown solid, the 4-aminobenzeneboronic acid pinacol ester, the tetrakis (triphenylphosphine) palladium, the potassium carbonate and the dioxane/water mixed solution is 5 mol; the dosage ratio of the yellow brown solid, dichloromethane, N-diisopropylethylamine and chloroacetyl chloride is 5 mol.
Further, in the step (1), the washing is sequentially carried out by using a saturated sodium bicarbonate solution, water and ethanol; the drying is vacuum drying at 50-70 ℃ for 10-14 h.
Further, the extracting agent extracted in the step (2) is a mixed solution of methanol and dichloromethane which are mixed according to the volume ratio of 1:9; washing is carried out by using saturated sodium bicarbonate solution and saturated brine; drying is drying by anhydrous sodium sulfate; purifying into column chromatography, wherein the solvent is mixed solution of ethyl acetate and n-hexane according to the volume ratio of 1:3.
Further, in the step (3), the extractant extracted is dichloromethane; the washing is carried out by using saturated sodium bicarbonate solution and saturated brine; drying is drying by anhydrous sodium sulfate; the purification is column chromatography, and the solvent is a mixed solution of methanol and dichloromethane according to the volume ratio of 1.
The invention also provides application of the compound capable of inducing apoptosis of macrovacuoles in preparation of drugs for treating tumors.
Further, tumors include colon cancer, lung adenocarcinoma, cervical cancer, liver cancer, breast cancer and glioma cells.
The invention has the beneficial effects that:
the 2-chloro-N- (4- (pyrazole [1,5-a ] pyrimidine-6-yl) phenyl) acetamide of the invention has the effect of inducing tumor cell death, and the cell death is caused by the formation of a plurality of huge vacuoles in cells induced by the compound and is called macrovesicular death. The compound has higher clinical application value and good development prospect, and can be used for treating tumor diseases. The invention also provides a method for synthesizing the compound (2-chloro-N- (4- (pyrazole [1,5-a ] pyrimidine-6-yl) phenyl) acetamide) simply and conveniently in a large scale.
Drawings
FIG. 1 is a graph of the effect of 2-chloro-N- (4- (pyrazole [1,5-a ] pyrimidin-6-yl) phenyl) acetamide on induction of macrocyst death in various tumor cells and HFC in normal cells (where tumor cells include colon cancer cell HCT116, lung adenocarcinoma cell H1975, cervical cancer cell Hela, liver cancer cell Hep3B, breast cancer cell MCF-7, glioma cell U87MG and U251; helPPA is 2-chloro-N- (4- (pyrazole [1,5-a ] pyrimidin-6-yl) phenyl) acetamide);
FIG. 2 is a graph of the cellular proliferation of 2-chloro-N- (4- (pyrazolo [1,5-a ] pyrimidin-6-yl) phenyl) acetamide (COPPA) in the inhibition of breast cancer cells MDA-MB-231;
FIG. 3 is a graph of the effect of 2-chloro-N- (4- (pyrazole [1,5-a ] pyrimidin-6-yl) phenyl) acetamide (COPPA) on the growth and body weight of MDA-MB-231 subcutaneous tumor inhibition of breast cancer cells (A) is a photograph of the breast cancer cells MDA-MB-231 subcutaneous tumor inhibition of COPPA; B is a statistical graph of the breast cancer cells MDA-MB-231 subcutaneous tumor inhibition of COPPA; and (C) is a graph of the effect of COPPA on the body weight of BALB/C-nu mice);
FIG. 4 is a scheme showing the preparation of 2-chloro-N- (4- (pyrazolo [1,5-a ] pyrimidin-6-yl) phenyl) acetamide (COPPA);
FIGS. 5 to 6 are mass spectrograms in steps (2) and (3) in the example of the present invention in this order;
FIGS. 7-9 are nuclear magnetic spectra of 2-chloro-N- (4- (pyrazolo [1,5-a ] pyrimidin-6-yl) phenyl) acetamide.
Detailed Description
The following detailed description of embodiments of the invention refers to the accompanying drawings.
Example 1
A process for the preparation of 2-chloro-N- (4- (pyrazolo [1,5-a ] pyrimidin-6-yl) phenyl) acetamide comprising the steps of:
(1) 30mmol 2-bromomalondialdehyde and 30mmol 5-aminopyrazole were added successively to 36ml ethanol in an ice water bath, and after stirring for 5min, 4ml 12mmol/ml concentrated hydrochloric acid was added dropwise, followed by reaction at room temperature for 6h, followed by filtration, and the filter cake was washed successively with 20ml saturated sodium bicarbonate solution, 20ml water, 6ml ethanol and repeated 1 time, followed by vacuum drying at 60 ℃ for 12h to give 5.70g (yield: 96%) of a light brown solid.
(2) Mixing 5mmol of the light brown solid obtained in the step (1), 5mmol of 4-aminophenylboronic acid pinacol ester, 5mmol of tetrakis (triphenylphosphine) palladium and 7.5mmol of potassium carbonate, adding 12ml of dioxane/water mixed solution (wherein the volume ratio of dioxane to water is 5:1), reacting at 80 ℃ for 8h under the protection of nitrogen, evaporating (40 ℃,0.5 h) to remove the solvent, extracting the residue with 80ml of methanol/dichloromethane mixed solution (wherein the volume ratio of methanol to dichloromethane is 1:9), washing with 80ml of saturated sodium bicarbonate solution and 80ml of saturated common salt water, drying with 6g of anhydrous sodium sulfate, and purifying by column chromatography (the solvent is 1.2L of mixed solution of ethyl acetate and n-hexane according to the volume ratio of 1:3) to obtain 0.86g of a yellow brown solid (yield: 82%); 1 H NMR(400MHz,DMSO)δ9.21(d,J＝2.2Hz,1H),8.84(d,J＝2.2Hz,1H),8.17(d,J＝2.3Hz,1H),7.60(d,J＝2.7Hz,1H),7.51(d,J＝8.4Hz,2H),6.68(d,J＝8.8Hz,2H),5.38(s,2H)ppm.MS(ESI,m/z):211[M+H] + ,252[M+CH 3 CN+H] + 。
(3) Dissolving 5mmol of the yellowish brown solid obtained in the step (2) in 40ml of dichloromethane, adding 6.5mmol of N, N-diisopropylethylamine, cooling for 10min in an ice water bath, dropwise adding 6mmol of chloroacetyl chloride, reacting at room temperature for 2h under the protection of nitrogen, extracting with 80ml of dichloromethane, washing with 80ml of saturated sodium bicarbonate solution and 80ml of saturated saline solution, drying with 6g of anhydrous sodium sulfate, and performing column chromatography (the solvents are methanol and dichloromethane)1.5L of a mixed solution of an alkane and 49 in a volume ratio of 1 to 1) was purified, to obtain 1.26 g of a pale yellow solid (yield: 88%). 1 H NMR(400MHz,DMSO)δ10.48(s,1H),9.44(s,1H),8.94(s,1H),8.25(s,1H),7.84(d,J＝8.2Hz,2H),7.73(d,J＝8.2Hz,2H),6.77(s,1H),4.30(s,2H)ppm. 13 C NMR(101MHz,DMSO)δ164.87,149.19,146.93,145.30,138.65,131.98,128.88,127.39,120.91,119.88,96.12,43.65ppm.MS(ESI,m/z):287[M+H] + ,328[M+CH 3 CN+H] + 。
Example 2
A process for the preparation of 2-chloro-N- (4- (pyrazolo [1,5-a ] pyrimidin-6-yl) phenyl) acetamide comprising the steps of:
(1) In an ice-water bath, 30mmol 2-bromomalondialdehyde and 30mmol 5-aminopyrazole are sequentially added into 36ml ethanol, stirred and reacted for 4min, then 4ml 12mmol/ml concentrated hydrochloric acid is dropwise added, the reaction is carried out for 5h at room temperature, then the filtration is carried out, then 20ml saturated sodium bicarbonate solution, 20ml water and 6ml ethanol are sequentially used for washing a filter cake, the repeated 1 time is carried out, and the vacuum drying is carried out for 14h at 50 ℃ to obtain light brown solid;
(2) Mixing 5mmol of the light brown solid obtained in the step (1), 5mmol of 4-aminophenylboronic acid pinacol ester, 5mmol of tetrakis (triphenylphosphine) palladium and 7.5mmol of potassium carbonate, adding 12ml of dioxane/water mixed solution (wherein the volume ratio of dioxane to water is 5:1), reacting at 70 ℃ for 9h under the protection of nitrogen, evaporating (40 ℃,0.5 h) to remove the solvent, extracting the residue with 80ml of methanol/dichloromethane mixed solution (wherein the volume ratio of methanol to dichloromethane is 1:9), washing with 80ml of saturated sodium bicarbonate solution and 80ml of saturated saline, drying with 6g of sodium sulfate, and purifying by anhydrous column chromatography (the solvent is 1.2L of mixed solution of ethyl acetate and n-hexane according to the volume ratio of 1:3) to obtain a yellow brown solid;
(3) Dissolving 5mmol of the yellowish brown solid obtained in the step (2) in 40ml of dichloromethane, adding 6.5mmol of N, N-diisopropylethylamine, cooling for 8min in an ice water bath, dropwise adding 6mmol of chloroacetyl chloride, reacting at room temperature for 1.5h under the protection of nitrogen, extracting with 80ml of dichloromethane, washing with 80ml of saturated sodium bicarbonate solution and 80ml of saturated saline solution, drying with 6g of anhydrous sodium sulfate, and purifying by column chromatography (the solvent is 1.5L of a mixed solution of methanol and dichloromethane in a volume ratio of 1.
Example 3
A process for the preparation of 2-chloro-N- (4- (pyrazolo [1,5-a ] pyrimidin-6-yl) phenyl) acetamide comprising the steps of:
(1) In an ice water bath, 30mmol 2-bromomalondialdehyde and 30mmol 5-aminopyrazole are sequentially added into 36ml ethanol, and are stirred for reaction for 6min, then 4ml 12mmol/ml concentrated hydrochloric acid is dropwise added, reaction is carried out for 7h at room temperature, then filtration is carried out, the filter cake is sequentially washed by 20ml saturated sodium bicarbonate solution, 20ml water and 6ml ethanol, and the washing is repeated for 1 time, and vacuum drying is carried out for 10h at 70 ℃ to obtain light brown solid;
(2) Mixing 5mmol of the light brown solid obtained in the step (1), 5mmol of 4-aminophenylboronic acid pinacol ester, 5mmol of tetrakis (triphenylphosphine) palladium and 7.5mmol of potassium carbonate, adding 12ml of dioxane/water mixed solution (wherein the volume ratio of dioxane to water is 5:1), reacting at 90 ℃ for 7h under the protection of nitrogen, evaporating (40 ℃,0.5 h) to remove the solvent, extracting the residue with 80ml of methanol/dichloromethane mixed solution (wherein the volume ratio of methanol to dichloromethane is 1:9), washing with 80ml of saturated sodium bicarbonate solution and 80ml of saturated saline, drying with 6g of sodium sulfate, and purifying by anhydrous column chromatography (the solvent is 1.2L of mixed solution of ethyl acetate and n-hexane according to the volume ratio of 1:3) to obtain a yellow brown solid;
(3) Dissolving 5mmol of the yellowish brown solid obtained in the step (2) in 40ml of dichloromethane, adding 6.5mmol of N, N-diisopropylethylamine, cooling in an ice water bath for 12min, dropwise adding 6mmol of chloroacetyl chloride, reacting at room temperature for 2.5h under the protection of nitrogen, extracting with 80ml of dichloromethane, washing with 80ml of saturated sodium bicarbonate solution and 80ml of saturated saline solution, drying with 6g of anhydrous sodium sulfate, and purifying by column chromatography (the solvent is 1.5L of a mixed solution of methanol and dichloromethane in a volume ratio of 1.
Experimental example 1
2-chloro-N- (4- (pyrazolo [1,5-a ] pyrimidin-6-yl) phenyl) acetamide (COPPA) induces megavesicular death in tumor cells:
respectively culturing the colon cancer cell HCT116 and the lung adenocarcinoma cell H1975. Inoculating cervical cancer cell Hela, hepatocarcinoma cell Hep3B, breast cancer cell MCF-7, glioma cells U87MG and U251 and normal colon cell FHC in 96-well plate at 3000/well, placing the cells in CO 2 In an incubator (37 ℃, 5% 2 ) The culture was carried out overnight. CoPPA was then added to the different tumor cells to a final concentration of 1. Mu.M, an equal volume of DMSO was added to the control wells, and the cells were incubated for an additional 12 hours. And finally, photographing by using a high content photographing system, and observing the vacuole formation and cell death conditions in the cells. The results are shown in FIG. 1, with red arrows indicating the formation of large vacuoles within the cells. 1 mu M COPPA induces the formation of a large number of vacuoles in tumor cells and induces the cells to undergo macrovesicular death; without any effect on normal colon FHC cells.
Experimental example 2
2-chloro-N- (4- (pyrazole [1,5-a ] pyrimidine-6-yl) phenyl) acetamide (COPPA) inhibits proliferation of breast cancer cells MDA-MB-231:
inoculating breast cancer cell MDA-MB-231 into 96-well plate at 3000/well, and placing the cell in CO 2 In an incubator (37 ℃, 5% CO) 2 ) The culture was carried out overnight. The experimental group was added with 2-chloro-N- (4- (pyrazole [1,5-a)]Pyrimidin-6-yl) phenyl) acetamide (COPPA) was added to give final concentrations of 0.5, 1, 2, 5, 10, 20, 40 μ M, and a control was added with a corresponding volume of DMSO. After 48 hours of further incubation 10. Mu.L MTT solution per well was added and incubation continued for 4 hours, the medium was aspirated and 200. Mu.L DMSO reagent was added, shaking the flask (10 min at 300 rpm); OD value at 570nm was read using a microplate reader (BioTek rotation 5), cell growth inhibition = (1-OD experiment/OD control) × 100%, and IC50 value was calculated using Graphpad Prism 8. The results showed that 2-chloro-N- (4- (pyrazole [1,5-a)]Pyrimidin-6-yl) phenyl) acetamide (COPPA) treatment for 48h had an IC50 value of 6.4. + -. 0.3. Mu.M for breast cancer cells MDA-MB-231.
Experimental example 3
2-chloro-N- (4- (pyrazolo [1,5-a ] pyrimidin-6-yl) phenyl) acetamide (COPPA) inhibits breast cancer cells MDA-MB-231 subcutaneous tumor growth:
BALB/c-nu female mice aged 4 weeks were housed in SPF-grade animal houses and the mice were inoculated subcutaneously into the upper left forelimb 10 7 MDA-MB-231 cells, awaiting swellingTumor size is about 100mm 3 When, mice were divided into: control group, COPPA 20mg/kg group and COPPA 40mg/kg group, and administration was performed. The administration mode comprises the following steps: administration to the abdominal cavity; administration volume: 100 mu L of the solution; the administration frequency is as follows: 3 days/time; the administration times are as follows: 10 times. And the body weight of the mice was recorded at the same time as the administration. Finally, the mice were sacrificed and the tumors were removed, photographed, and weighed. The experimental result is shown in figure 3, the COPPA can inhibit the growth of the subcutaneous tumor of MDA-MB-231, has obvious anti-tumor activity, and has no obvious toxic or side effect through weight display.
While the present invention has been described in detail with reference to the illustrated embodiments, it should not be construed as limited to the scope of the present patent. Various modifications and changes may be made by those skilled in the art without inventive step within the scope of the appended claims.
Claims (9)
1. A compound that induces apoptosis in a macrovesicle comprising: the compound is 2-chloro-N- (4- (pyrazole [1,5-a ] pyrimidine-6-yl) phenyl) acetamide with the chemical formula
2. The process for the preparation of a compound capable of inducing apoptosis of the cellular macroalves according to claim 1, comprising the steps of:
(1) Sequentially adding 2-bromomalonaldehyde and 5-aminopyrazole into ethanol in an ice water bath, stirring for reacting for 4-6 min, dropwise adding concentrated hydrochloric acid, reacting for 5-7 h at room temperature, filtering, washing a filter cake, and drying to obtain a light brown solid;
(2) Mixing the light brown solid obtained in the step (1), 4-aminobenzene boronic acid pinacol ester, tetrakis (triphenylphosphine) palladium and potassium carbonate, adding dioxane/water mixed solution, reacting at 70-90 ℃ for 7-9 h under the protection of inert gas, evaporating to remove the solvent, extracting, washing and drying the residue, and purifying to obtain a yellow brown solid;
(3) And (3) dissolving the yellowish-brown solid obtained in the step (2) in dichloromethane, adding N, N-diisopropylethylamine, cooling in an ice water bath for 8-12 min, dropwise adding chloroacetyl chloride, reacting at room temperature for 1.5-2.5 h under the protection of inert gas, and extracting, washing, drying and purifying to obtain the yellow brown liquid.
3. The method of claim 2, wherein: the light brown solid has the chemical formula
The yellow-brown solid has a chemical formula of
4. The method of claim 2, wherein: the dosage ratio of the 2-bromomalonaldehyde, the 5-aminopyrazole, the ethanol and the concentrated hydrochloric acid is 30mol; the dosage ratio of the light brown solid, the 4-aminobenzeneboronic acid pinacol ester, the tetrakis (triphenylphosphine) palladium, the potassium carbonate and the dioxane/water mixed solution is 5 mol; the dosage ratio of the yellow brown solid, dichloromethane, N-diisopropylethylamine and chloroacetyl chloride is 5 mol.
5. The method of claim 2, wherein: in the step (1), the washing is sequentially carried out by using a saturated sodium bicarbonate solution, water and ethanol; the drying is vacuum drying at 50-70 ℃ for 10-14 h.
6. The method of claim 2, wherein: in the step (2), the extracting agent is a mixed solution of methanol and dichloromethane which are mixed according to the volume ratio of 1:9; the washing is carried out by using a saturated sodium bicarbonate solution and a saturated saline solution; the drying is drying by anhydrous sodium sulfate; the purification is column chromatography, and the used solvent is mixed solution of ethyl acetate and n-hexane according to the volume ratio of 1:3.
7. The method of claim 2, wherein: in the step (3), the extractant for extraction is dichloromethane; the washing is carried out by using saturated sodium bicarbonate solution and saturated saline solution; the drying is drying by anhydrous sodium sulfate; the purification is column chromatography, and the used solvent is a mixed solution of methanol and dichloromethane according to the volume ratio of 1.
8. Use of a compound according to claim 1 for inducing apoptosis in a macrophage in the preparation of a medicament for treating a neoplasm.
9. Use according to claim 8, characterized in that: the tumor comprises colon cancer, lung adenocarcinoma, cervical cancer, liver cancer, breast cancer and glioma cells.
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