CN114957261B - Compound with anti-head and neck cancer effect and preparation method and application thereof - Google Patents
Compound with anti-head and neck cancer effect and preparation method and application thereof Download PDFInfo
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Abstract
The invention discloses a compound with an anti-head and neck cancer effect, a preparation method and application thereof, wherein the compound is named as 2- (4- (3-bromopyrazol [1,5-a ] pyrimidine-6-yl) phenyl) acetic acid. The compound has the effects of obviously inhibiting proliferation of head and neck cancer cells and promoting apoptosis of the head and neck cancer cells, so that the compound has higher clinical application value and good development prospect, and can be used for treating head and neck cancer. The preparation method of the invention is simple and convenient and is suitable for mass synthesis.
Description
Technical Field
The invention belongs to the technical field of medicinal chemistry, and particularly relates to a compound with an anti-head and neck cancer effect, and a preparation method and application thereof.
Background
Head and neck cancer is the seventh most common cancer type worldwide, with over 60% of patients already in the middle and late stages when first diagnosed, and very high mortality, one of the major diseases affecting human life and health. Currently, methods for treating head and neck cancer clinically include surgical treatment, chemotherapeutic drugs, targeted therapy, immunotherapy, etc., however, these treatment strategies have the following problems: the cranio-maxillofacial-brain exposure can be caused after the large-scale surgical excision, and the survival quality and survival rate of patients are seriously affected; chemotherapy drugs are prone to cause tumor resistance, and patients have poor prognosis; targeted therapy has the defects of molecular typing, off-target and the like; thus, there is a clinical lack of effective treatments for head and neck cancer. Therefore, the development of a novel medicine with the effect of resisting the head and neck cancer has very important significance.
Disclosure of Invention
Aiming at the prior art, the invention provides a compound with the effect of resisting head and neck cancer, a preparation method and application thereof, so as to develop a novel medicament with the effect of resisting head and neck cancer.
In order to achieve the above purpose, the technical scheme adopted by the invention is as follows: provides a compound with the effect of resisting head and neck cancer, the name of the compound is 2- (4- (3-bromopyrazol [1,5-a ] pyrimidine-6-yl) phenyl) acetic acid, and the chemical formula is that
The invention also provides a preparation method of the compound with the effect of resisting head and neck cancer, which comprises the following steps:
(1) Sequentially adding 2-bromopropionaldehyde and 5-aminopyrazole into ethanol in ice water bath, stirring and reacting for 4-6 min, then dropwise adding concentrated hydrochloric acid, reacting for 5-7 h at room temperature, and then filtering, washing a filter cake and drying to obtain light brown solid;
(2) Mixing the light brown solid obtained in the step (1), 4-borate-methyl phenylacetate, tetra (triphenylphosphine) palladium and potassium carbonate, adding dioxane/water mixed solution, reacting for 7-9 hours at 70-90 ℃ under the protection of inert gas, evaporating to remove solvent, extracting, washing and drying residues, and purifying to obtain light yellow solid;
(3) Dissolving the pale yellow solid obtained in the step (2) in dichloromethane, carrying out ice water bath for 8-12 min, adding N-bromosuccinimide, reacting for 0.8-1.2 h at room temperature, and carrying out extraction, washing, drying and purification to obtain the pale yellow solid;
(4) Dissolving the pale yellow solid obtained in the step (3) in a methanol/water mixed solution, adding LiOH to react for 4-6 hours at 50-70 ℃, adjusting the pH value of the mixture to 3-4, filtering, washing a filter cake, and drying to obtain the catalyst.
On the basis of the technical scheme, the invention can be improved as follows.
Further, the light brown solid was
The pale yellow solid in the step (2) is
The pale yellow solid in the step (3) is +.>
Further, the dosage ratio of 2-bromopropionaldehyde, 5-aminopyrazole, ethanol and concentrated hydrochloric acid is 30mol:30mol:36L:4ml, wherein the concentration of the concentrated hydrochloric acid is 12 mol/liter; the dosage ratio of the light brown solid, the methyl 4-borate-phenylacetate, the tetra (triphenylphosphine) palladium, the potassium carbonate and the dioxane/water mixed solution is 4mol:4.2mol:0.4mol:6mol:15ml, wherein the volume ratio of the dioxane to the water in the dioxane/water mixed solution is 5:1; the dosage ratio of the light yellow solid, the methylene dichloride and the N-bromosuccinimide in the step (3) is 2.3mol:40L:2.4mol; the ratio of light yellow solid, methanol/water mixture and LiOH in step (4) was 1.7mol:16L:6.1mol.
Further, in the step (1), washing is carried out by using saturated sodium bicarbonate solution, water and ethanol in sequence; drying is carried out for 10 to 14 hours at the temperature of 50 to 70 ℃ in vacuum.
In the step (2), the extracting agent is mixed liquid of methanol and dichloromethane according to the volume ratio of 1:9; washing with saturated sodium bicarbonate solution and saturated saline; 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 1:4.
Further, in the step (3), the extracting agent for extraction is dichloromethane; washing with saturated sodium bicarbonate solution and saturated saline; drying with anhydrous sodium sulfate; the purification is column chromatography, and the solvent is mixed solution of dichloromethane and n-hexane according to the volume ratio of 1:3.
Further, in the step (4), the washing is washing with water and ethanol; drying is carried out for 10 to 14 hours at the temperature of 50 to 70 ℃ in vacuum.
The invention also provides application of the compound with the effect of resisting the head and neck cancer in preparing a medicine for resisting the head and neck cancer.
The beneficial effects of the invention are as follows:
the compound 2- (4- (3-bromopyrazol [1,5-a ] pyrimidine-6-yl) phenyl) acetic acid has the effects of obviously inhibiting proliferation of head and neck cancer cells and promoting apoptosis of the head and neck cancer cells, so that the compound has higher clinical application value and good development prospect, and can be used for treating the head and neck cancer. The invention also provides a simple and convenient method suitable for synthesizing a large amount of 2- (4- (3-bromopyrazol [1,5-a ] pyrimidine-6-yl) phenyl) acetic acid.
Drawings
FIG. 1 shows the effect of 2- (4- (3-bromopyrazol [1,5-a ] pyrimidin-6-yl) phenyl) acetic acid of the invention in inhibiting proliferation of head and neck cancer cells SCC15 and Cal 33;
FIG. 2 shows the in vitro clonal formation of 2- (4- (3-bromopyrazol [1,5-a ] pyrimidin-6-yl) phenyl) acetic acid inhibiting head and neck cancer SCC15 and Cal33 cells according to the invention;
FIGS. 3-5 are graphs showing that 2- (4- (3-bromopyrazol [1,5-a ] pyrimidin-6-yl) phenyl) acetic acid of the invention promotes apoptosis of head and neck cancer SCC15 and Cal33 cells;
FIG. 6 is a flow chart of the preparation of 2- (4- (3-bromopyrazol [1,5-a ] pyrimidin-6-yl) phenyl) acetic acid according to the invention;
FIGS. 7 to 8 are nuclear magnetic patterns of the product obtained in the step (3) of the present invention;
FIGS. 9 to 10 are nuclear magnetic patterns of 2- (4- (3-bromopyrazol [1,5-a ] pyrimidin-6-yl) phenyl) acetic acid according to the invention;
fig. 11 to 13 are mass spectra in steps (2), (3) and (4) in this order in the examples of the present invention.
Detailed Description
The following describes the embodiments of the present invention in detail with reference to the drawings.
Example 1
A process for the preparation of 2- (4- (3-bromopyrazol [1,5-a ] pyrimidin-6-yl) phenyl) acetic acid comprising the steps of:
(1) 30mmol of 2-bromopropionaldehyde and 30mmol of 5-aminopyrazole were successively added to 36ml of ethanol in an ice-water bath and reacted under stirring for 5 minutes, followed by dropwise addition of 4ml of 12mmol/ml of concentrated hydrochloric acid, further reaction at room temperature for 6 hours, followed by filtration, washing of the cake with 20ml of saturated sodium hydrogencarbonate solution, 20ml of water, 6ml of ethanol successively and repetition of 1 time, further vacuum drying at 60℃for 12 hours, to give 5.70g of a pale brown solid (yield: 96%).
(2) Mixing 4mmol of the light brown solid obtained in the step (1), 4.2mmol of 4-borate-methyl phenylacetate, 0.4mmol of tetrakis (triphenylphosphine) palladium and 6mmol of potassium carbonate, adding 15ml of dioxane/water mixed solution (the volume ratio of dioxane to water is 5:1), reacting for 8 hours at 80 ℃ under the protection of nitrogen, evaporating again (40 ℃ for 0.5 hours) to remove the solvent, extracting the residue by 80ml of methanol/dichloromethane mixed solution (the volume ratio of methanol to dichloromethane is 1:9), washing by 80ml of saturated sodium bicarbonate solution and 80ml of saturated saline, drying by 6g of anhydrous sodium sulfate, and purifying by column chromatography (the solvent is 1.5L of mixed solution of ethyl acetate and n-hexane according to the volume ratio of 1:4), thereby obtaining 1.95 g (yield: 89%) of light yellow solid; MS (ESI, m/z): 268[ M+H ]] + ,309[M+CH 3 CN+H] + 。
(3) 2.3mmol of the pale yellow solid obtained in the step (2) was dissolved in 40ml of methylene chloride, followed by an ice-water bath for 10 minutes, then 2.4mmol of N-bromosuccinimide was added to react for 1 hour at room temperature, and after extraction with 40ml of methylene chloride, washing with 40ml of saturated sodium bicarbonate solution and 40ml of saturated sodium sulfate, drying with 4g of anhydrous sodium sulfate, further purification by column chromatography (solvent: 1.5L of a mixed solution of methylene chloride and N-hexane in a volume ratio of 1:3) was carried out, 0.60 g (yield: 75%) of pale yellow solid was obtained. 1 H NMR(400MHz,DMSO)δ9.51(d,J＝2.2Hz,1H),9.02(d,J＝2.2Hz,1H),8.42(s,1H),7.81(d,J＝8.3Hz,2H),7.43(d,J＝8.3Hz,2H),3.77(s,2H),3.63(s,3H)ppm. 13 C NMR(101MHz,DMSO)δ171.45,150.63,144.92,143.74,134.84,133.12,131.68,130.23,127.00,122.00,99.51,82.93,51.76ppm.MS(ESI,m/z):387[M+CH 3 CN+H] + 。
(4) 1.7mmol of the pale yellow solid obtained in step (3) are dissolved in 16ml of a methanol/water mixture (wherein the volume ratio of methanol to water is 1:1), and 6.1mmol of LiOH. H is added 2 O was reacted at 60℃for 5 hours, after which the pH of the mixture was adjusted to 3.5, and then filtered, after which the cake was washed successively with 2ml of water and 2ml of ethanol, and dried under vacuum at 60℃for 12 hours to give 0.57 g (yield: 99%) of a white solid. 1 H NMR(400MHz,DMSO)δ9.50(d,J＝2.1Hz,1H),9.02(d,J＝2.0Hz,1H),8.41(s,1H),7.78(d,J＝8.1Hz,2H),7.40(d,J＝8.1Hz,2H),3.59(s,2H)ppm. 13 C NMR(101MHz,DMSO)δ172.53,150.63,144.84,143.70,132.96,131.08,130.20,129.84,126.74,122.17,82.87ppm.MS(ESI,m/z):332[M+H] + ,375[M+CH 3 CN+H] + 。
Example 2
A process for the preparation of 2- (4- (3-bromopyrazol [1,5-a ] pyrimidin-6-yl) phenyl) acetic acid comprising the steps of:
(1) In ice water bath, sequentially adding 30mmol 2-bromopropionaldehyde and 30mmol 5-aminopyrazole into 36ml ethanol, stirring and reacting for 4min, then dropwise adding 4ml 12mmol/ml concentrated hydrochloric acid, reacting at room temperature for 5h, filtering, sequentially washing a filter cake with 20ml saturated sodium bicarbonate solution, 20ml water and 6ml ethanol for 1 time, and vacuum drying at 50 ℃ for 14h to obtain light brown solid;
(2) After mixing 4mmol of the light brown solid obtained in the step (1), 4.2mmol of 4-borate-methyl phenylacetate, 0.4mmol of tetrakis (triphenylphosphine) palladium and 6mmol of potassium carbonate, adding 15ml of dioxane/water mixed solution (wherein the volume ratio of dioxane to water is 5:1), reacting for 9 hours at 70 ℃ under the protection of nitrogen, evaporating again (40 ℃ for 0.5 hours) to remove the solvent, extracting the residue by 80ml of methanol/dichloromethane mixed solution (wherein the volume ratio of methanol to dichloromethane is 1:9), washing by 80ml of saturated sodium bicarbonate solution and 80ml of saturated saline solution, drying by 6g of anhydrous sodium sulfate, and purifying by column chromatography (wherein the solvent is 1.5L of mixed solution of ethyl acetate and n-hexane according to the volume ratio of 1:4), thereby obtaining pale yellow solid;
(3) Dissolving 2.3mmol of the pale yellow solid obtained in the step (2) in 40ml of dichloromethane, carrying out ice water bath for 8min, adding 2.4mmol of N-bromosuccinimide, reacting for 0.8h at room temperature, extracting by 40ml of dichloromethane, washing by 40ml of saturated sodium bicarbonate solution and 40ml of saturated saline water, drying by 4g of anhydrous sodium sulfate, and purifying by column chromatography (the solvent is a mixed solution of dichloromethane and N-hexane according to the volume ratio of 1:3, namely 1.5L), thus obtaining the pale yellow solid;
(4) 1.7mmol of the pale yellow solid obtained in step (3) was dissolved in 16ml of a methanol/water mixture (wherein the volumes of methanol and water wereIn a ratio of 1:1), 6.1mmol LiOH H are additionally added 2 O was reacted at 50℃for 6 hours, then the pH of the mixture was adjusted to 4, and then filtered, and thereafter the cake was washed successively with 2ml of water and 2ml of ethanol, and dried in vacuo at 50℃for 14 hours to give a white solid.
Example 3
A process for the preparation of 2- (4- (3-bromopyrazol [1,5-a ] pyrimidin-6-yl) phenyl) acetic acid comprising the steps of:
(1) In ice water bath, sequentially adding 30mmol 2-bromopropionaldehyde and 30mmol 5-aminopyrazole into 36ml ethanol, stirring and reacting for 6min, then dropwise adding 4ml 12mmol/ml concentrated hydrochloric acid, reacting at room temperature for 7h, filtering, sequentially washing a filter cake with 20ml saturated sodium bicarbonate solution, 20ml water and 6ml ethanol for 1 time, and vacuum drying at 70 ℃ for 10h to obtain light brown solid;
(2) After mixing 4mmol of the light brown solid obtained in the step (1), 4.2mmol of 4-borate-methyl phenylacetate, 0.4mmol of tetrakis (triphenylphosphine) palladium and 6mmol of potassium carbonate, adding 15ml of dioxane/water mixed solution (wherein the volume ratio of dioxane to water is 5:1), reacting for 7h at 90 ℃ under the protection of nitrogen, evaporating again (40 ℃ for 0.5 h), removing the solvent, extracting the residue by 80ml of methanol/dichloromethane mixed solution (wherein the volume ratio of methanol to dichloromethane is 1:9), washing by 80ml of saturated sodium bicarbonate solution and 80ml of saturated saline solution, drying by 6g of anhydrous sodium sulfate, and purifying by column chromatography (wherein the solvent is 1.5L of mixed solution of ethyl acetate and n-hexane according to the volume ratio of 1:4), thereby obtaining pale yellow solid;
(3) Dissolving 2.3mmol of the pale yellow solid obtained in the step (2) in 40ml of dichloromethane, carrying out ice water bath for 8min, adding 2.4mmol of N-bromosuccinimide, reacting for 1.2h at room temperature, extracting by 40ml of dichloromethane, washing by 40ml of saturated sodium bicarbonate solution and 40ml of saturated saline water, drying by 4g of anhydrous sodium sulfate, and purifying by column chromatography (the solvent is a mixed solution of dichloromethane and N-hexane in a volume ratio of 1:3, namely 1.5L), thus obtaining the pale yellow solid;
(4) 1.7mmol of the pale yellow solid obtained in step (3) are dissolved in 16ml of a methanol/water mixture (wherein the volume ratio of methanol to water is 1:1), and 6.1mmol of LiOH. H is added 2 O is reacted for 4 hours at the temperature of 70 ℃,the pH of the mixture was then adjusted to 4, filtered, and the filter cake was washed sequentially with 2ml water and 2ml ethanol and dried in vacuo at 70℃for 10h to give a white solid.
Experimental example 1
2- (4- (3-bromopyrazol [1,5-a ] pyrimidin-6-yl) phenyl) acetic acid (BPPA) inhibits proliferation of head and neck cancer SCC15 and Cal33 cells:
head and neck cancer cells SCC15 and Cal33 were seeded at 3000 cells/well in 96-well plates and placed in CO 2 In incubator (37 ℃, 5% CO) 2 ) Culturing overnight. BPPA was added to the experimental group to a final concentration of 0.1, 0.3, 0.6, 1.25, 2.5, 5, 10 μm, and DMSO was added to the control group in the corresponding volume. After 48 hours of further incubation, 10. Mu.L MTT solution was added to each well and incubation continued for 4 hours, medium was aspirated off and 200. Mu.L MSO reagent was added, shaking (10 min at 300 rpm); OD values at 570nm were read using a microplate reader (BioTek station 5), cell growth inhibition = (1-OD experiment/OD control) X100% and IC50 values were calculated using Graphpad Prism 8. As a result, as shown in FIG. 1, the IC50 values for the head and neck cancer cells SCC15 and Cal33 at 48h of BPPA treatment were 1.6.+ -. 0.2. Mu.M and 1.4.+ -. 0.1. Mu.M, respectively.
Experimental example 2
2- (4- (3-bromopyrazol [1,5-a ] pyrimidin-6-yl) phenyl) acetic acid (BPPA) inhibits head and neck cancer cell SCC15 and Cal33 clone formation:
SCC15 and Cal33 cells were counted and inoculated into 6-well plates at 1000 cells per well, and after 24h inoculation, 0, 1. Mu.M, 2.5. Mu.M, 5. Mu.M small molecule compounds were added, respectively, and placed at 37℃and 5% CO 2 Culturing in an incubator for about 14d; the supernatant was discarded, the cells were fixed with 4% paraformaldehyde, stained with crystal violet for 30min, and washed 3 times with pbs for 2min each. And scanning the experimental result by a scanner, and carrying out statistical analysis. The results are shown in fig. 2, BPPA has the ability to inhibit colon cancer cell clonogenesis and has a dose dependency (×p < 0.01).
Experimental example 3
Flow cytometry analysis 2- (4- (3-bromopyrazol [1,5-a ] pyrimidin-6-yl) phenyl) acetic acid (BPPA) promoted apoptosis:
taking SCC15 and Cal33 cells in logarithmic growth phase, digesting, counting, and culturing at 5×10 5 Inoculating into the hole/holeIn a 6-well plate, CO 2 Culturing in an incubator for 24 hours; adding BPPA compound to make its final concentration be 1. Mu.M, 2.5. Mu.M and 5. Mu.M respectively, setting 3 compound holes for each concentration, and continuously culturing for 24 hr; collecting the culture medium containing the drug, collecting cells in the same EP tube, centrifuging at 1000r/min for 5min, discarding supernatant, and adjusting cell concentration to 10 with Binding buffer 6 individual/mL; 100 mu L of 10 6 Cell suspension at a concentration of individual/mL, 5. Mu.L of annexin V-FITC and 5. Mu.L of PI were added, and left at room temperature for 15min in the absence of light; after staining in dark for 30min, apoptosis was detected by the machine, and 50000 cells were detected per sample. The results are shown in FIGS. 3-5, where the number of apoptosis increases as the concentration of BPPA compound increases.
Although specific embodiments of the invention have been described in detail with reference to the accompanying drawings, it should not be construed as limiting the scope of protection of the present patent. Various modifications and variations which may be made by those skilled in the art without the creative effort are within the scope of the patent described in the claims.
Claims (8)
1. A compound having an anti-head and neck cancer effect, characterized in that: the compound is named as 2- (4- (3-bromopyrazol [1,5-a ] pyrimidine-6-yl) phenyl) acetic acid, and has a chemical formula of
2. The method for preparing a compound having an anti-head and neck cancer effect according to claim 1, comprising the steps of:
(1) Sequentially adding 2-bromopropionaldehyde and 5-aminopyrazole into ethanol in ice water bath, stirring and reacting for 4-6 min, then dropwise adding concentrated hydrochloric acid, reacting for 5-7 h at room temperature, and then filtering, washing a filter cake and drying to obtain light brown solid;
(2) Mixing the light brown solid obtained in the step (1), 4-borate-methyl phenylacetate, tetra (triphenylphosphine) palladium and potassium carbonate, adding dioxane/water mixed solution, reacting for 7-9 hours at 70-90 ℃ under the protection of inert gas, evaporating to remove solvent, extracting, washing and drying residues, and purifying to obtain light yellow solid;
(3) Dissolving the pale yellow solid obtained in the step (2) in dichloromethane, carrying out ice water bath for 8-12 min, adding N-bromosuccinimide, reacting for 0.8-1.2 h at room temperature, and carrying out extraction, washing, drying and purification to obtain the pale yellow solid;
(4) Dissolving the pale yellow solid obtained in the step (3) in a methanol/water mixed solution, adding LiOH to react for 4-6 hours at 50-70 ℃, adjusting the pH value of the mixture to 3-4, filtering, washing a filter cake, and drying to obtain the catalyst;
the light brown solid is
The pale yellow solid in the step (2) is
The pale yellow solid in the step (3) is
3. The preparation method according to claim 2, characterized in that: the dosage ratio of the 2-bromopropionaldehyde, the 5-aminopyrazole, the ethanol and the concentrated hydrochloric acid is 30mol:30mol:36L:4L, wherein the concentration of the concentrated hydrochloric acid is 12 mol/L; the dosage ratio of the light brown solid to the 4-borate-methyl phenylacetate to the tetra (triphenylphosphine) palladium to the potassium carbonate to the dioxane/water mixed solution is 4mol:4.2mol:0.4mol:6mol:15L, wherein the volume ratio of the dioxane to the water in the dioxane/water mixed solution is 5:1; the dosage ratio of the light yellow solid, the methylene dichloride and the N-bromosuccinimide in the step (3) is 2.3mol:40L:2.4mol; the ratio of light yellow solid, methanol/water mixture and LiOH in step (4) was 1.7mol:16L:6.1mol.
4. The preparation method according to claim 2, characterized in that: in the step (1), the washing is sequentially performed by using saturated sodium bicarbonate solution, water and ethanol; the drying is vacuum drying for 10-14 h at 50-70 ℃.
5. The preparation method according to claim 2, characterized in that: in the step (2), the extracted extractant is mixed liquid of methanol and dichloromethane according to the volume ratio of 1:9; the washing is carried out by using saturated sodium bicarbonate solution and saturated saline water; the drying is drying by 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 1:4.
6. The preparation 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 saturated sodium bicarbonate solution and saturated saline water; the drying is drying by anhydrous sodium sulfate; the purification is column chromatography, and the solvent is mixed solution of dichloromethane and n-hexane according to the volume ratio of 1:3.
7. The preparation method according to claim 2, characterized in that: in the step (4), the washing is washing with water and ethanol; the drying is vacuum drying for 10-14 h at 50-70 ℃.
8. The use of a compound having an anti-head and neck cancer effect according to claim 1 for the preparation of an anti-head and neck cancer medicament.
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| CN114957261A (en) | 2022-08-30 |
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