CN114751910A - Compound capable of inducing cell megacyst type 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- (pyrazolo [1,5-a ] pyrimidine-6-yl) phenyl) acetamide. The 2-chloro-N- (4- (pyrazolo [1,5-a ] pyrimidin-6-yl) phenyl) acetamide of the invention has the effect of inducing tumor cell death caused by the compound inducing the formation of numerous large vacuoles in cells, which 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 large numbers of 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 technical scheme adopted by the invention is as follows: provides a compound capable of inducing apoptosis of the cellular megaloplasma, which is 2-chloro-N- (4- (pyrazolo [1,5-a ] pyrimidine-6-yl) phenyl) acetamide and has a chemical formula
The invention also provides a preparation method of the compound capable of inducing cell megaloplasma death, which comprises the following steps:
(1) sequentially adding 2-bromomalondialdehyde 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 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.
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
Further, the dosage ratio of the 2-bromomalonaldehyde, the 5-aminopyrazole, the ethanol and the concentrated hydrochloric acid is 30mol:30mol:36L:4ml, wherein the concentration of the concentrated hydrochloric acid is 12 mol/L; the dosage ratio of the light brown solid, 4-aminobenzene pinacol ester, tetrakis (triphenylphosphine) palladium, potassium carbonate and dioxane/water mixed liquor is 5mol:5mol:5mol:7.5mol:12ml, wherein the volume ratio of dioxane to water in the dioxane/water mixed liquor is 5: 1; the amount ratio of the yellowish brown solid, dichloromethane, N-diisopropylethylamine and chloroacetyl chloride was 5mol:40L:6.5mol:6 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 extractant extracted in the step (2) is a mixed solution of methanol and dichloromethane in a volume ratio of 1: 9; washing is carried out by using saturated sodium bicarbonate solution and saturated brine; drying is drying with anhydrous sodium sulfate; the purification is column chromatography, and 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 extracting agent 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 in a volume ratio of 1: 49.
The invention also provides application of the compound capable of inducing cell megaloplasma death in preparation of a medicament for treating tumors.
Further, the tumors include colon cancer, lung adenocarcinoma, cervical cancer, liver cancer, breast cancer and glioma cells.
The beneficial effects of the invention are:
the 2-chloro-N- (4- (pyrazolo [1,5-a ] pyrimidin-6-yl) phenyl) acetamide of the invention has the effect of inducing tumor cell death, which is caused by the compound inducing the formation of numerous giant vacuoles in cells, and is called macrofoam type 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 simply and conveniently synthesizing the compound (2-chloro-N- (4- (pyrazolo [1,5-a ] pyrimidine-6-yl) phenyl) acetamide) in large scale.
Drawings
FIG. 1 is a graph showing the effect of 2-chloro-N- (4- (pyrazolo [1,5-a ] pyrimidin-6-yl) phenyl) acetamide on inducing macrophage-type death of various tumor cells and on normal HFC (wherein the 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; COPPA is 2-chloro-N- (4- (pyrazolo [1,5-a ] pyrimidin-6-yl) phenyl) acetamide);
FIG. 2 is a graph of the inhibition of breast cancer cell MDA-MB-231 by 2-chloro-N- (4- (pyrazolo [1,5-a ] pyrimidin-6-yl) phenyl) acetamide (COPPA) on cell proliferation;
FIG. 3 is a graph showing the effect of 2-chloro-N- (4- (pyrazolo [1,5-a ] pyrimidin-6-yl) phenyl) acetamide (COPPA) on the inhibition of the growth of the subcutaneous tumor of breast cancer cells MDA-MB-231 and the body weight of animals (wherein, the graph (A) is a photograph showing that COPPA inhibits the subcutaneous tumor of breast cancer cells MDA-MB-231; the graph (B) is a statistical graph showing that COPPA inhibits the subcutaneous tumor of breast cancer cells MDA-MB-231; and the graph (C) is a graph showing 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;
FIGS. 7 to 9 show 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) in an ice water bath, 30mmol of 2-bromomalondialdehyde and 30mmol of 5-aminopyrazole are sequentially added into 36ml of ethanol, and after stirring and reacting for 5min, 4ml of concentrated hydrochloric acid with 12mmol/ml is dropwise added, reaction is carried out for 6h at room temperature, filtering is carried out, the filter cake is sequentially washed by 20ml of saturated sodium bicarbonate solution, 20ml of water and 6ml of ethanol and repeated for 1 time, and vacuum drying is carried out for 12h at 60 ℃ to obtain 5.70g of light brown solid (yield: 96%).
(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 ℃, 0.5h) 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 in a volume ratio of 1: 3) to obtain 0.86g of a yellow brown solid (yield: 82%);1H 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+CH3CN+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, 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: 49) to obtain 1.26 g of a pale yellow solid (yield: 88%). 1H 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.13C 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+CH3CN+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) sequentially adding 30mmol of 2-bromomalondialdehyde and 30mmol of 5-aminopyrazole into 36ml of ethanol in an ice water bath, stirring for reacting for 4min, dropwise adding 4ml of 12mmol/ml concentrated hydrochloric acid, reacting for 5h at room temperature, filtering, sequentially washing a filter cake with 20ml of saturated sodium bicarbonate solution, 20ml of water and 6ml of ethanol, repeating for 1 time, and performing vacuum drying at 50 ℃ for 14h 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 ℃, 0.5h) 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 solution, 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 in a 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: 49) to obtain a pale yellow solid.
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) sequentially adding 30mmol of 2-bromomalondialdehyde and 30mmol of 5-aminopyrazole into 36ml of ethanol in an ice water bath, stirring for reacting for 6min, then dropwise adding 4ml of concentrated hydrochloric acid with the concentration of 12mmol/ml, reacting for 7h at room temperature, filtering, sequentially washing a filter cake with 20ml of saturated sodium bicarbonate solution, 20ml of water and 6ml of ethanol, repeating for 1 time, and performing vacuum drying at 70 ℃ for 10h to obtain 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 90 ℃ for 7h under the protection of nitrogen, evaporating (40 ℃, 0.5h) 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 solution, 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 in a 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: 49) to obtain a pale yellow solid.
Experimental example 1
2-chloro-N- (4- (pyrazolo [1,5-a ] pyrimidin-6-yl) phenyl) acetamide (COPPA) induces megavesicular death of tumor cells:
respectively inoculating the cultured colon cancer cell HCT116, lung adenocarcinoma cell H1975, cervical cancer cell Hela, liver cancer cell Hep3B, breast cancer cell MCF-7, glioma cells U87MG and U251 and normal colon cell FHC in a 96-well plate at 3000/well, placing the cells in CO2Incubator (37 ℃, 5% CO)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- (pyrazolo [1,5-a ] pyrimidin-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 CO2Incubator (37 ℃, 5% CO)2) The culture was carried out overnight. The experimental group was added with 2-chloro-N- (4- (pyrazolo [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 continuous culture, adding 10 mul MTT solution into each well, continuously incubating for 4 hours, sucking out the culture medium, adding 200 mul DMSO reagent, and shaking the table (shaking at 300rpm for 10 min); OD at 570nm was read using a microplate reader (BioTek staining 5) and the cell growth inhibition was ═ (1-OD experiment/OD control) × 100%, and IC50 values were calculated using Graphpad Prism 8. The results showed that 2-chloro-N- (4- (pyrazolo [1,5-a ]]The IC50 value of the breast cancer cell MDA-MB-231 after 48h of treatment by pyrimidine-6-yl) phenyl) acetamide (COPPA) is 6.4 ±. + -0.3μM。
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 7MDA-MB-231 cells with a tumor size of about 100mm3When, mice were divided into: control group, COPPA 20mg/kg group and COPPA 40mg/kg group were administered. The administration mode comprises the following steps: administration to the abdominal cavity; administration volume: 100 mu L of the solution; dosing frequency: 3 days/time; the frequency of administration is 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 MDA-MB-231 subcutaneous tumor, 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- (pyrazolo [1,5-a ] pyrimidine-6-yl) phenyl) acetamide and has a 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-bromomalondialdehyde and 5-aminopyrazole into ethanol in an ice water bath, stirring for reacting for 4-6 min, dropwise adding concentrated hydrochloric acid, reacting at room temperature for 5-7 h, 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 production method according to claim 2, characterized in that: the light brown solid has a chemical formula of
The yellow brown solid has a chemical formula of
4. The production method according to claim 2, characterized in that: the dosage ratio of the 2-bromomalondialdehyde to the 5-aminopyrazole to the ethanol to the concentrated hydrochloric acid is 30mol:30mol:36L:4ml, wherein the concentration of the concentrated hydrochloric acid is 12 mol/L; the dosage ratio of the light brown solid, 4-aminobenzene pinacol ester, tetrakis (triphenylphosphine) palladium, potassium carbonate and dioxane/water mixed solution is 5mol:5mol:5mol:7.5mol:12ml, wherein the volume ratio of dioxane to water in the dioxane/water mixed solution is 5: 1; the dosage ratio of the yellow brown solid, dichloromethane, N-diisopropylethylamine and chloroacetyl chloride is 5mol:40L:6.5mol:6 mol.
5. The production method according to claim 2, characterized in that: 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 production method according to claim 2, characterized in that: in the step (2), the extracting agent is a mixed solution of methanol and dichloromethane in a volume ratio of 1: 9; 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 ethyl acetate and n-hexane according to the volume ratio of 1: 3.
7. The production method according to claim 2, characterized in that: in the step (3), the extracting agent for extraction is dichloromethane; 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 a mixed solution of methanol and dichloromethane in a volume ratio of 1: 49.
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 includes colon cancer, lung adenocarcinoma, cervical cancer, liver cancer, breast cancer and glioma cell.
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