CN119930494A - Aromatic compound and its preparation method and application in preparing anti-inflammatory and anti-tumor drugs - Google Patents
Aromatic compound and its preparation method and application in preparing anti-inflammatory and anti-tumor drugs Download PDFInfo
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Abstract
The invention belongs to the technical field of medicines and synthesis, and particularly relates to an aryl compound, a preparation method thereof and application thereof in preparing anti-inflammatory and anti-tumor medicines. The invention constructs a novel compound with anti-inflammatory and anti-tumor curative effect by covalent bond connection with natural anti-inflammatory active compound containing phenylboronic acid, which can be used as a medicine for treating liver cancer, and an inflammation regulator improves the anti-cancer curative effect by adding the natural anti-inflammatory active compound with the organic boronic acid compound with tumor activity. The preparation method provided by the invention has the advantages of simple steps, convenience in operation and good feasibility, and has the potential of large-scale industrial application and wide market prospect. The invention also provides application of the aryl compound in the scheme or the aryl compound obtained by the preparation method in the scheme in preparation of anti-inflammatory and anti-tumor drugs. The aryl compound provided by the invention has good anticancer effect, can be used for preparing anti-inflammatory and anti-tumor drugs, and has good social benefit.
Description
Technical Field
The invention belongs to the technical field of medicines and synthesis, and particularly relates to an aryl compound, a preparation method thereof and application thereof in preparing anti-inflammatory and anti-tumor medicines.
Background
Hepatocellular carcinoma (HCC) is the sixth most common malignancy worldwide, and has high morbidity and mortality. Over the last decade, some molecular targeted drugs have been FDA approved for the treatment of advanced HCC patients (e.g., the kinase inhibitor sorafenib, the angiogenesis inhibitor mab), and although these drugs have proven to be useful as adjuvant therapies, they have not been very therapeutic, and for some patients, only a few months of survival can be prolonged. Therefore, there is an increasing need for low-toxicity and high-efficiency drug development for treating liver cancer.
Natural compounds of plant origin, in agreement, are considered as a reliable and consistent source of anticancer lead drug research. Natural products are generally high in safety, cinnamic acid (CINNAMIC ACID, CA) and ferulic acid derivatives (Ferulic acid, FA) are chemical substances with biological activity, are phenolic acids commonly existing in plants, and have proved to have anti-inflammatory and antibacterial activities. Indole-3-acetic acid, also known as Indoleacetic Acid (IA), is an auxin. One study reported the role of oral IA in diet-induced non-alcoholic fatty liver disease (NAFLD) mice models, and the results indicate that IA has significant efficacy in reducing steatosis and inflammation, with IA being likely to be a safe therapeutic option for NAFLD.
Innate and adaptive immunity in inflammatory responses play an important role in tumorigenesis, progression and metastasis, and thus, therapy-induced inflammatory responses also affect the clinical therapeutic effects of tumors to varying degrees. However, the conventional anti-inflammatory drugs have limited curative effects for definitely treating tumors, and cannot completely inhibit the development of the tumors and eliminate the tumors.
Disclosure of Invention
The invention aims to provide an aryl compound, a preparation method thereof and application thereof in preparing anti-inflammatory and anti-tumor medicaments.
In order to achieve the above object, the present invention provides the following technical solutions:
the invention provides an aryl compound, the structure of which is shown as a formula CA-1, a formula FA-1 or a formula IA-1:
;
In the formula CA-1, the formula FA-1 or the formula IA-1, R is a group of the formula a, a group of the formula b or a group of the formula c (pentagram is a connecting site);
。
Preferably, the aryl compound comprises one of a compound of formula CA-1a, a compound of formula CA-1b, a compound of formula CA-1c, a compound of formula FA-1a, a compound of formula FA-1b, a compound of formula FA-1c, a compound of formula IA-1a, a compound of formula IA-1b and a compound of formula IA-1 c;
。
the invention also provides a preparation method of the aryl compound, which comprises the following steps:
Mixing raw materials, 1-hydroxybenzotriazole, carbodiimide and a poor solvent for esterification reaction to obtain a solution A containing an intermediate compound, wherein the structure of the intermediate compound is shown as a formula Z:
;
Mixing the solution A and the solution B for amidation reaction to obtain the aryl compound, wherein the solution B comprises a base catalyst, a benzene derivative and a good solvent, and the benzene derivative is meta-aminophenylboric acid, meta-aminophenyl methanol, meta-aminobenzoic acid methyl ester, aniline or benzylamine;
The crude drug comprises a compound shown in a formula CA, a compound shown in a formula FA or a compound shown in a formula IA;
。
preferably, the mass ratio of the bulk drug to the 1-hydroxybenzotriazole is 200-1000:180-1200.
Preferably, the mass ratio of the bulk drug to the carbodiimide is 200-1000:210-1400.
Preferably, the mass volume ratio of the bulk drug to the poor solvent is (200-1000) mg (4-20) mL.
Preferably, the concentration of the benzene derivative in the solution B is 9.5-465 mg/mL.
Preferably, the mass ratio of the raw material medicine to the benzene derivative in the solution B is 50-2000:60-2400.
Preferably, the amidation reaction is carried out under stirring for 20-36 h.
The invention also provides application of the aryl compound in the scheme or the aryl compound obtained by the preparation method in the scheme in preparation of anti-inflammatory and anti-tumor drugs.
The present invention provides an aryl compound. The invention constructs a novel compound with anti-inflammatory and anti-tumor curative effect by covalent bond connection with natural anti-inflammatory active compound containing phenylboronic acid, which can be used as a medicine for treating liver cancer, and an inflammation regulator improves the anti-cancer curative effect by adding the natural anti-inflammatory active compound with the organic boronic acid compound with tumor activity.
The invention also provides a preparation method of the aryl compound. The preparation method provided by the invention has the advantages of simple steps, convenience in operation and good feasibility, and has the potential of large-scale industrial application and wide market prospect.
The invention also provides application of the aryl compound in the scheme or the aryl compound obtained by the preparation method in the scheme in preparation of anti-inflammatory and anti-tumor drugs. The aryl compound provided by the invention has good anticancer effect, can be used for preparing anti-inflammatory and anti-tumor drugs, and has good social benefit.
Drawings
In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings that are needed in the embodiments will be briefly described below, and it is obvious that the drawings in the following description are only some embodiments of the present invention, and other drawings may be obtained according to these drawings without inventive effort for a person skilled in the art.
FIG. 1 is a 1 H NMR spectrum of a compound of formula CA-1a prepared in example 1 of the invention;
FIG. 2 is a 1 H NMR spectrum of a compound of formula CA-1b prepared in example 2 of the present invention;
FIG. 3 is a 1 H NMR spectrum of a compound of formula CA-1c prepared in example 3 of the invention;
FIG. 4 is a 1 H NMR spectrum of a compound of formula FA-1a prepared in example 4 according to the present invention;
FIG. 5 is a 1 H NMR spectrum of a compound of formula FA-1b prepared in example 5 of the present invention;
FIG. 6 is a 1 H NMR spectrum of a compound of formula FA-1c prepared in example 6 of the present invention;
FIG. 7 is a 1 H NMR spectrum of a compound of formula IA-1a prepared according to example 7 of the present invention;
FIG. 8 is a 1 H NMR spectrum of a compound of formula IA-1b prepared according to example 8 of the present invention;
FIG. 9 is a 1 H NMR spectrum of a compound of formula IA-1c prepared according to example 9 of the present invention;
FIG. 10 is an MS spectrum of a compound of formula CA-1a prepared in example 1 of the present invention;
FIG. 11 is an MS spectrum of a compound of formula CA-1b prepared in example 2 of the present invention;
FIG. 12 is an MS spectrum of a compound of formula CA-1c prepared in example 3 of the present invention;
FIG. 13 is an MS spectrum of the compound of formula FA-1a prepared in example 4 of the present invention;
FIG. 14 is an MS spectrum of the compound of formula FA-1b prepared in example 5 of the present invention;
FIG. 15 is an MS spectrum of the compound of formula FA-1c prepared in example 6 of the present invention;
FIG. 16 is an MS spectrum of a compound of formula IA-1a prepared according to example 7 of the present invention;
FIG. 17 is an MS spectrum of a compound of formula IA-1b prepared according to example 8 of the present invention;
FIG. 18 is an MS spectrum of a compound of formula IA-1c prepared according to example 9 of the present invention;
FIG. 19 shows the antitumor activity of cinnamic acid and the compounds prepared in examples 1-3;
FIG. 20 shows the antitumor activity of the compounds prepared in examples 4 to 6;
FIG. 21 shows the antitumor activity of indole-3 acetic acid and the compounds prepared in examples 7 to 9.
Detailed Description
The invention provides an aryl compound, the structure of which is shown as a formula CA-1, a formula FA-1 or a formula IA-1:
;
In the formula CA-1, the formula FA-1 or the formula IA-1, R is a group of the formula a, a group of the formula b or a group of the formula c (pentagram is a connecting site);
。
In the present invention, the aryl compound preferably includes one of a compound of formula CA-1a, a compound of formula CA-1b, a compound of formula CA-1c, a compound of formula FA-1a, a compound of formula FA-1b, a compound of formula FA-1c, a compound of formula IA-1a, a compound of formula IA-1b and a compound of formula IA-1 c;
。
the invention also provides a preparation method of the aryl compound, which comprises the following steps:
Mixing raw materials, 1-hydroxybenzotriazole, carbodiimide and a poor solvent for esterification reaction to obtain a solution A containing an intermediate compound, wherein the structure of the intermediate compound is shown as a formula Z:
;
And mixing the solution A and the solution B for amidation reaction to obtain the aryl compound, wherein the solution B comprises a base catalyst, a benzene derivative and a good solvent, and the benzene derivative is meta-aminophenylboric acid, meta-aminophenyl methanol, meta-aminobenzoic acid methyl ester, aniline or benzylamine.
The invention mixes the raw material medicine, 1-Hydroxybenzotriazole (HOBT), carbodiimide and poor solvent (marked as mixture A) for esterification reaction to obtain solution A containing intermediate compound.
In the invention, the bulk drug preferably comprises a compound shown in a formula CA, a compound shown in a formula FA or a compound shown in a formula IA;
。
in the invention, the mass ratio of the bulk drug to the 1-hydroxybenzotriazole is preferably 200-1000:180-1200, more preferably 300-900:180.2-1181.2, further preferably 400-700:199.8-998.9, further preferably 500-600:236.2-901.2. The invention improves the reaction speed of the intermediate after DCC activation through 1-hydroxybenzotriazole.
In the invention, the mass ratio of the bulk drug to the carbodiimide is preferably 200-1000:210-1400, more preferably 200-1000:212.2-1390.4, further preferably 200-1000:235.2-1175.95, and further preferably 200-1000:278.1-1060.8. According to the invention, the carboxyl is activated by carbodiimide, so that the leaving property of the O end is increased, and the urea derivative is easier to leave, thereby promoting the formation of an amide bond or an ester bond.
In the present invention, the poor solvent preferably includes one or more of tetrahydrofuran and N, N-dimethylformamide.
In the invention, the mass volume ratio of the bulk drug to the poor solvent is preferably (200-1000) mg (4-20) mL, more preferably (400-800) mg (8-15) mL, and even more preferably (500-700) mg (10-12) mL.
In the invention, the mixture A is preferably prepared by adding a raw material medicine to tetrahydrofuran and mixing (marked as first mixing) to obtain a premix, then adding 1-hydroxybenzotriazole to the premix and mixing (marked as second mixing) to obtain a mixture, and then adding carbodiimide to the mixture while stirring at 500-700 rpm (marked as third mixing).
In the invention, the first mixing is preferably stirring mixing, and the rotation speed of the stirring mixing is preferably 500-700 rpm, more preferably 550-650 rpm, further preferably 600 rpm, and the mixing time is preferably 20-60 s, more preferably 30-50 s, further preferably 40 s.
In the present invention, the second mixing is preferably performed under ice bath conditions, the second mixing is preferably stirring mixing, and the rotation speed of the stirring mixing is preferably 500 to 700 rpm, more preferably 550 to 650 rpm, still more preferably 600rpm, until the 1-hydroxybenzotriazole is dissolved.
In the present invention, the third mixing is preferably performed under ice bath conditions, the third mixing is preferably stirring mixing, and the rotation speed of the stirring mixing is preferably 500 to 700 rpm, more preferably 550 to 650 rpm, further preferably 600 rpm, and the mixing time is preferably 20 to 60 minutes, more preferably 25 to 45 minutes, further preferably 30 min.
In the present invention, the esterification reaction is preferably performed under ice bath conditions, and the reaction time is preferably within 30min, more preferably 20 to 30 minutes.
In the present invention, in the solution B, the base catalyst is preferably nitrogen-methylmorpholine.
In the present invention, in the solution B, the good solvent preferably includes one or more of dioxane, tetrahydrofuran and N, N-dimethylformamide.
In the present invention, the concentration of the benzene derivative in the solution B is preferably 9.5 to 465 mg/mL, more preferably 15 to 400 mg/mL, further preferably 50 to 300 mg/mL, further preferably 150 to 200 mg/mL.
In the present invention, the solution B is preferably prepared by mixing a base catalyst and a good solvent to obtain a premix, and adding a benzene derivative to the premix for mixing (referred to as mixing B). The invention adopts the alkali catalyst to provide alkaline environment, activates amino groups in benzene derivatives, and generates interaction with substrates through proton transfer, thereby being beneficial to the formation of amide bonds and accelerating the rate of chemical reaction, and further improving the efficiency of condensation reaction.
In the invention, the mixing B is preferably stirring and mixing, the rotating speed of the stirring and mixing is preferably 500-700 rpm, more preferably 550-650 rpm, the mixing time is preferably 10-60 min, more preferably 30min, and the temperature of the mixing B is preferably room temperature.
After the solution A is obtained, the solution A and the solution B are mixed for amidation reaction to obtain the aryl compound. In the invention, the mass ratio of the raw material medicine to the benzene derivative in the solution B is preferably 50-2000:60-2400, more preferably 100-1500:120-1800, and even more preferably 200-1000:240-1200.
In the invention, the temperature of the amidation reaction is preferably room temperature, the reaction time is preferably 20 to 36 hours, more preferably 24 to 32 hours, further preferably 27 to 30 hours, the amidation reaction is preferably performed under stirring, and the stirring speed is preferably 500 to 700 rpm, more preferably 550 to 650 rpm, further preferably 600 rpm. According to the invention, whether the reaction is complete or not is detected by TLC (ethyl acetate: petroleum ether=1:1-2).
In the present invention, the amidation reaction is preferably further followed by subjecting the obtained reaction product to solid-liquid separation and solid purification in this order.
In the present invention, the solid-liquid separation is preferably reduced pressure distillation after filtration, and the pressure of the reduced pressure distillation is preferably 50 to 200 mbar, more preferably 80 to 150 mbar, still more preferably 100 to 120 mbar, and the temperature is preferably 25 to 50 ℃, more preferably 30 to 45 ℃, still more preferably 40 ℃. The invention removes Dicyclohexylurea (DCU) and tetrahydrofuran by solid-liquid separation.
In the present invention, the solid purification preferably includes washing and recrystallization in sequence.
In the present invention, the washing is preferably performed by dissolving the solid, washing, recovering the ethyl acetate layer, drying, and then sequentially filtering and concentrating the filtrate.
In the present invention, the reagent used for dissolution of the solid is preferably Ethyl Acetate (EA).
In the present invention, the washing is preferably performed by washing the solution obtained by dissolving the solid with saturated aqueous sodium bicarbonate, saturated aqueous sodium chloride, saturated aqueous sodium bisulfate, saturated aqueous sodium chloride, saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride, respectively, in this order.
In the present invention, the number of times of washing is independently preferably 3 or more.
In the invention, the drying is preferably anhydrous sodium sulfate drying, the filtering is preferably suction filtration, and the suction filtration is preferably normal pressure suction filtration. The invention removes anhydrous sodium sulfate by normal pressure suction filtration.
In the present invention, the filtrate concentration is preferably reduced pressure concentration, the reduced pressure concentration is preferably 50 to 200 mbar, more preferably 70 to 160 mbar, still more preferably 90 to 140 mbar, still more preferably 100 to 120 mbar, the temperature is preferably 25 to 50 ℃, more preferably 30 to 45 ℃, still more preferably 40 ℃, and the filtrate concentration is preferably concentrated to dryness.
In the invention, the recrystallization is preferably carried out by re-dissolving the solid obtained by cleaning, then sequentially carrying out recrystallization, filtration and filter cake recovery, wherein the reagent used for re-dissolving is preferably dichloromethane, the recrystallization is preferably PE recrystallization, and the filtration is preferably normal pressure suction filtration.
The invention also provides application of the aryl compound in the scheme or the aryl compound obtained by the preparation method in the scheme in preparation of anti-inflammatory and anti-tumor drugs.
The aryl compound provided by the invention has good anticancer effect, can be used for preparing anti-inflammatory and anti-tumor drugs, and has good social benefit.
The following detailed description of the embodiments of the invention is provided in connection with the accompanying drawings and examples to further illustrate the invention, but should not be construed as limiting the scope of the invention.
In the specific examples and test cases of the present invention, the specifications and sources of the reagents used are:
Cinnamic acid (CA, lot: C832420, purity: 99%), ferulic acid (FA, lot: F809522, purity: 99%), indole-3-acetic acid (IA, lot: I6311, purity: 98%), meta-aminophenylboronic acid (Lot: 1028866, purity: 98%) were purchased from Shanghai Milin Biochemical technologies Co., ltd., (Lot: 1028866, purity: 99%), benzylamine (Lot: B108477, purity: 99%) was purchased from Ara Ding Shiji (Shanghai) Co., ltd.;
Carbodiimide (DCC) and 1-Hydroxybenzotriazole (HOBT) are commercially available from Shanghai, honghai, N-methylmorpholine (NMM), tetrahydrofuran (THF), petroleum Ether (PE), ethyl Acetate (EA), dichloromethane (DCM), sodium bicarbonate, sodium chloride, potassium bisulfate and anhydrous sodium sulfate are commercially available from Beijing Chemicals;
fetal Bovine Serum (FBS), DMEM and trypsin were purchased from Gibco, dimethyl sulfoxide (DMSO) was purchased from Shanghai Milin Biochemical technologies Co., ltd, and CCK-8 kit was purchased from Beijing Soy Bao technologies Co.
Example 1
First, a compound represented by the formula CA of 500 mg was added to tetrahydrofuran (10 mL) and dissolved with stirring, HOBT of 456 mg was added and completely dissolved in an ice bath, DCC of 696 mg was slowly added and stirred for 30min, and esterification reaction was carried out for 30min under ice bath conditions to obtain a solution A. 463 mg meta-aminophenylboronic acid was added to 2 mL NMM and stirred at room temperature for 30min to give solution B.
Solution a and solution B were then mixed at room temperature and stirred for reaction 24h, showing the disappearance of the CA starting point under TLC (ethyl acetate: petroleum ether=1:1). Dicyclohexylurea (DCU) was filtered off and tetrahydrofuran was evaporated off under reduced pressure. The solid was dissolved in 50mL Ethyl Acetate (EA), the resulting solution was washed three times with saturated aqueous sodium bicarbonate, saturated aqueous sodium chloride, saturated aqueous sodium bisulfate, saturated aqueous sodium chloride, saturated aqueous sodium bicarbonate, saturated aqueous sodium chloride, respectively, the ethyl acetate layer was dried over anhydrous sodium sulfate, the drying agent was removed by filtration under reduced pressure, and the filtrate was concentrated to dryness under reduced pressure. The obtained solid is redissolved by DCM, PE is recrystallized, suction filtration is carried out at normal pressure, and a filter cake is recovered to obtain the compound of the formula CA-1 a.
Yield of the Compound of formula CA-1a ：93.1%.ESI-MS(m/z):266.35 [M-H]-;1H NMR (300 MHz, DMSO): δ （ppm）=10.17 (s, 1H), 7.91 (dd, J = 5.3, 1.7 Hz, 2H), 7.68 – 7.61 (m, 2H), 7.58 – 7.38 (m, 4H), 7.31 (t, J = 7.7 Hz, 1H), 6.87 (d, J = 15.7 Hz, 1H).
Example 2
First, a compound represented by the formula CA of 500 mg was added to tetrahydrofuran (10 mL) and dissolved with stirring, HOBT of 456 mg was added and completely dissolved in an ice bath, DCC of 696 mg was slowly added and stirred for 30min, and esterification reaction was carried out for 30min under ice bath conditions to obtain a solution A. To NMM of 2mL was added 315 mg aniline and stirred at room temperature for 30min to give solution B.
Solution a and solution B were then mixed at room temperature and stirred for reaction 24h, showing the disappearance of the CA starting point under TLC (ethyl acetate: petroleum ether=1:1). Dicyclohexylurea (DCU) was filtered off and tetrahydrofuran was evaporated off under reduced pressure. The solid was dissolved in 50mL Ethyl Acetate (EA), the resulting solution was washed three times with saturated aqueous sodium bicarbonate, saturated aqueous sodium chloride, saturated aqueous sodium bisulfate, saturated aqueous sodium chloride, saturated aqueous sodium bicarbonate, saturated aqueous sodium chloride, respectively, the ethyl acetate layer was dried over anhydrous sodium sulfate, the drying agent was removed by filtration under reduced pressure, and the filtrate was concentrated to dryness under reduced pressure. The obtained solid is redissolved by DCM, PE is recrystallized, suction filtration is carried out at normal pressure, and a filter cake is recovered to obtain the compound of the formula CA-1 b.
Yield of the Compound of formula CA-1b ：63.72%,ESI-MS(m/z):224.21 [M＋H]+;1H NMR (300 MHz, DMSO) δ 10.20 (s, 1H), 7.91 – 7.54 (m, 5H), 7.54 – 7.29 (m, 5H), 7.17 – 6.96 (m, 1H), 6.85 (d, J = 15.7 Hz, 1H).
Example 3
First, a compound represented by the formula CA of 500 mg was added to tetrahydrofuran (10 mL) and dissolved with stirring, HOBT of 456 mg was added and completely dissolved in an ice bath, DCC of 696 mg was slowly added and stirred for 30 min, and esterification reaction was carried out for 30 min under ice bath conditions to obtain a solution A. 362. 362 mg benzylamine was added to 2 mL NMM and stirred at room temperature for 30. 30 min to give solution B.
Solution a and solution B were then mixed at room temperature and stirred for reaction 24h, showing the disappearance of the CA starting point under TLC (ethyl acetate: petroleum ether=1:1). Dicyclohexylurea (DCU) was filtered off and tetrahydrofuran was evaporated off under reduced pressure. The solid was dissolved in 50mL Ethyl Acetate (EA), the resulting solution was washed three times with saturated aqueous sodium bicarbonate, saturated aqueous sodium chloride, saturated aqueous sodium bisulfate, saturated aqueous sodium chloride, saturated aqueous sodium bicarbonate, saturated aqueous sodium chloride, respectively, the ethyl acetate layer was dried over anhydrous sodium sulfate, the drying agent was removed by filtration under reduced pressure, and the filtrate was concentrated to dryness under reduced pressure. The obtained solid is redissolved by DCM, PE is recrystallized, suction filtration is carried out at normal pressure, and a filter cake is recovered to obtain the compound of the formula CA-1 c.
Yield of the Compound of formula CA-1c ：59.49%.ESI-MS(m/z):238.12[M＋H]+;1H NMR (300 MHz, DMSO) δ 8.62 (t, J = 6.0 Hz, 1H), 7.64 – 7.53 (m, 2H), 7.52 – 7.16 (m, 9H), 6.70 (d, J = 15.8 Hz, 1H), 4.41 (d, J = 5.9 Hz, 2H).
Example 4
First, a compound represented by formula FA of 500 mg was added to tetrahydrofuran (10 mL) and dissolved with stirring, HOBT of 348 mg was added and completely dissolved in an ice bath, DCC of 531 mg was slowly added and stirring was continued for 30 min, and esterification reaction was performed for 30 min under ice bath conditions to obtain a solution a. 353. 353 mg m-aminophenylboronic acid was added to 2 mL of NMM and stirred at room temperature for 30. 30 min to give solution B.
Solution a and solution B were then mixed at room temperature and stirred for reaction 24h, showing the disappearance of FA starting material points under TLC (ethyl acetate: petroleum ether=1:1). Dicyclohexylurea (DCU) was filtered off and tetrahydrofuran was evaporated off under reduced pressure. The solid was dissolved in 50 mL Ethyl Acetate (EA), the resulting solution was washed three times with saturated aqueous sodium bicarbonate, saturated aqueous sodium chloride, saturated aqueous sodium bisulfate, saturated aqueous sodium chloride, saturated aqueous sodium bicarbonate, saturated aqueous sodium chloride, respectively, the ethyl acetate layer was dried over anhydrous sodium sulfate, the drying agent was removed by filtration under reduced pressure, and the filtrate was concentrated to dryness under reduced pressure. The obtained solid is redissolved by DCM, PE is recrystallized, suction filtration is carried out at normal pressure, and a filter cake is recovered, thus obtaining the compound of the formula FA-1 a.
Yield of the Compound of formula FA-1a ：37.38%.ESI-MS(m/z):312.53 [M-H]-;1H NMR (300 MHz, DMSO) δ 10.01 (s, 1H), 8.14 (s, 1H), 7.94 – 7.81 (m, 2H), 7.53 – 7.42 (m, 2H), 7.29 (s, 1H), 7.18 (d, J = 1.9 Hz, 1H), 7.05 (d, J = 1.9 Hz, 1H), 6.86 – 6.61 (m, 2H), 3.83 (s, 3H).
Example 5
First, a compound represented by formula FA of 500 mg was added to tetrahydrofuran (10 mL) and dissolved with stirring, HOBT of 348 mg was added and completely dissolved in an ice bath, DCC of 531 mg was slowly added and stirring was continued for 30min, and esterification reaction was performed for 30min under ice bath conditions to obtain a solution a. 240 mg aniline was added to 2 mL NMM and stirred at room temperature for 30, 30min to give solution B.
Solution a and solution B were then mixed at room temperature and stirred for reaction 24h, showing the disappearance of FA starting material points under TLC (ethyl acetate: petroleum ether=1:1). Dicyclohexylurea (DCU) was filtered off and tetrahydrofuran was evaporated off under reduced pressure. The solid was dissolved in 50 mL Ethyl Acetate (EA), the resulting solution was washed three times with saturated aqueous sodium bicarbonate, saturated aqueous sodium chloride, saturated aqueous sodium bisulfate, saturated aqueous sodium chloride, saturated aqueous sodium bicarbonate, saturated aqueous sodium chloride, respectively, the ethyl acetate layer was dried over anhydrous sodium sulfate, the drying agent was removed by filtration under reduced pressure, and the filtrate was concentrated to dryness under reduced pressure. The obtained solid is redissolved by DCM, PE is recrystallized, suction filtration is carried out at normal pressure, and a filter cake is recovered, thus obtaining the compound of the formula FA-1 b.
Yield of the Compound of formula FA-1b ：66.55%,ESI-MS(m/z):270.20 [M＋H]+;1H NMR (300 MHz, DMSO) δ 10.07 (s, 1H), 9.52 (s, 1H), 7.83 – 7.57 (m, 2H), 7.49 (d, J = 15.6 Hz, 1H), 7.41 – 7.25 (m, 2H), 7.24 – 6.77 (m, 4H), 6.64 (d, J = 15.6 Hz, 1H), 3.83 (s, 3H).
Example 6
First, a compound represented by formula FA of 500 mg was added to tetrahydrofuran (10 mL) and dissolved with stirring, HOBT of 348 mg was added and completely dissolved in an ice bath, DCC of 531 mg was slowly added and stirring was continued for 30min, and esterification reaction was performed for 30min under ice bath conditions to obtain a solution a. 276 mg benzylamine was added to 2 mL NMM and stirred at room temperature for 30min to give solution B.
Solution a and solution B were then mixed at room temperature and stirred for reaction 24h, showing the disappearance of FA starting material points under TLC (ethyl acetate: petroleum ether=1:1). Dicyclohexylurea (DCU) was filtered off and tetrahydrofuran was evaporated off under reduced pressure. The solid was dissolved in 50 mL Ethyl Acetate (EA), the resulting solution was washed three times with saturated aqueous sodium bicarbonate, saturated aqueous sodium chloride, saturated aqueous sodium bisulfate, saturated aqueous sodium chloride, saturated aqueous sodium bicarbonate, saturated aqueous sodium chloride, respectively, the ethyl acetate layer was dried over anhydrous sodium sulfate, the drying agent was removed by filtration under reduced pressure, and the filtrate was concentrated to dryness under reduced pressure. The obtained solid is redissolved by DCM, PE is recrystallized, suction filtration is carried out at normal pressure, and a filter cake is recovered, thus obtaining the compound of the formula FA-1 c.
Yield of the Compound of formula FA-1c ：84.35%.ESI-MS(m/z):284.12[M＋H]+;1H NMR (300 MHz, DMSO) δ 8.44 (d, J = 6.0 Hz, 1H), 7.48 – 7.07 (m, 7H), 6.99 (dd, J = 8.2, 1.9 Hz, 1H), 6.78 (d, J = 8.1 Hz, 1H), 6.50 (d, J = 15.7 Hz, 1H), 4.38 (d, J = 5.9 Hz, 2H), 3.80 (s, 3H).
Example 7
First, a compound represented by formula IA of 500 mg was added to tetrahydrofuran (10 mL) and dissolved with stirring, HOBT of 386 mg was added and completely dissolved in an ice bath, DCC of 586 mg was slowly added and stirring was continued for 30min, and esterification reaction was performed for 30min under ice bath conditions to obtain a solution a. To NMM of 2 mL, 392 mg m-aminophenylboronic acid was added and stirred at room temperature for 30min to give solution B.
Solution a and solution B were then mixed at room temperature and stirred for reaction 24 h, showing disappearance of IA starting material points under TLC (ethyl acetate: petroleum ether=1:1). Dicyclohexylurea (DCU) was filtered off and tetrahydrofuran was evaporated off under reduced pressure. The solid was dissolved in 50 mL Ethyl Acetate (EA), the resulting solution was washed three times with saturated aqueous sodium bicarbonate, saturated aqueous sodium chloride, saturated aqueous sodium bisulfate, saturated aqueous sodium chloride, saturated aqueous sodium bicarbonate, saturated aqueous sodium chloride, respectively, the ethyl acetate layer was dried over anhydrous sodium sulfate, the drying agent was removed by filtration under reduced pressure, and the filtrate was concentrated to dryness under reduced pressure. The obtained solid is redissolved by DCM, PE is recrystallized, suction filtration is carried out at normal pressure, and a filter cake is recovered to obtain the compound of the formula IA-1 a.
Yield of the Compound of formula IA-1a ：30.34%.ESI-MS(m/z):293.32[M-H]-;1H NMR (300 MHz, DMSO) δ 10.97 – 10.87 (m, 1H), 10.01 (s, 1H), 7.99 (s, 1H), 7.86 – 7.81 (m, 1H), 7.78 – 7.69 (m, 1H), 7.62 (d, J = 7.8 Hz, 1H), 7.45 (dt, J = 7.4, 1.2 Hz, 1H), 7.38 – 7.31 (m, 1H), 7.27 – 7.20 (m, 1H), 7.09 – 6.94 (m, 2H), 3.71 (s, 2H).
Example 8
First, a compound represented by formula IA of 500 mg was added to tetrahydrofuran (10 mL) and dissolved with stirring, HOBT of 386 mg was added and completely dissolved in an ice bath, DCC of 586 mg was slowly added and stirring was continued for 30min, and esterification reaction was performed for 30min under ice bath conditions to obtain a solution a. 266 mg aniline was added to 2 mL NMM and stirred at room temperature for 30, 30min to give solution B.
Solution a and solution B were then mixed at room temperature and stirred for reaction 24 h, showing disappearance of IA starting material points under TLC (ethyl acetate: petroleum ether=1:1). Dicyclohexylurea (DCU) was filtered off and tetrahydrofuran was evaporated off under reduced pressure. The solid was dissolved in 50mL Ethyl Acetate (EA), the resulting solution was washed three times with saturated aqueous sodium bicarbonate, saturated aqueous sodium chloride, saturated aqueous sodium bisulfate, saturated aqueous sodium chloride, saturated aqueous sodium bicarbonate, saturated aqueous sodium chloride, respectively, the ethyl acetate layer was dried over anhydrous sodium sulfate, the drying agent was removed by filtration under reduced pressure, and the filtrate was concentrated to dryness under reduced pressure. The obtained solid is redissolved by DCM, PE is recrystallized, suction filtration is carried out at normal pressure, and a filter cake is recovered to obtain the compound of the formula IA-1 b.
Yield of the Compound of formula IA-1b ：57.33%,ESI-MS(m/z):251.26 [M＋H]+;1H NMR (300 MHz, DMSO) δ 10.91 (s, 1H), 10.09 (s, 1H), 7.67 – 7.53 (m, 3H), 7.40 – 7.21 (m, 4H), 7.13 – 6.92 (m, 3H), 3.72 (d, J = 0.8 Hz, 2H).
Example 9
First, a compound represented by formula IA of 500 mg was added to tetrahydrofuran (10 mL) and dissolved with stirring, HOBT of 386 mg was added and completely dissolved in an ice bath, DCC of 586 mg was slowly added and stirring was continued for 30min, and esterification reaction was performed for 30min under ice bath conditions to obtain a solution a. 306 mg benzylamine was added to 2 mL NMM and stirred at room temperature for 30min to give solution B.
Solution a and solution B were then mixed at room temperature and stirred for reaction 24 h, showing disappearance of IA starting material points under TLC (ethyl acetate: petroleum ether=1:1). Dicyclohexylurea (DCU) was filtered off and tetrahydrofuran was evaporated off under reduced pressure. The solid was dissolved in 50 mL Ethyl Acetate (EA), the resulting solution was washed three times with saturated aqueous sodium bicarbonate, saturated aqueous sodium chloride, saturated aqueous sodium bisulfate, saturated aqueous sodium chloride, saturated aqueous sodium bicarbonate, saturated aqueous sodium chloride, respectively, the ethyl acetate layer was dried over anhydrous sodium sulfate, the drying agent was removed by filtration under reduced pressure, and the filtrate was concentrated to dryness under reduced pressure. The obtained solid is redissolved by DCM, PE is recrystallized, suction filtration is carried out at normal pressure, and a filter cake is recovered to obtain the compound of the formula IA-1 c.
Yield of the Compound of formula IA-1c ：87.64%.ESI-MS(m/z):265.13[M＋H]+;1H NMR (300 MHz, DMSO) δ 8.44 (d, J = 6.0 Hz, 1H), 7.48 – 7.07 (m, 7H), 6.99 (dd, J = 8.2, 1.9 Hz, 1H), 6.78 (d, J = 8.1 Hz, 1H), 6.50 (d, J = 15.7 Hz, 1H), 4.38 (d, J = 5.9 Hz, 2H), 3.80 (s, 3H).
Test example 1
The structures of the compounds prepared in examples 1-9 are identified through 1 H NMR and mass spectrometry, and the results are shown in figures 1-18. The 1 H NMR results are shown in FIGS. 1 to 9, and the results are shown in FIGS. 10 to 18.
As can be seen from FIGS. 1 to 18, the present invention successfully prepares the compound of formula CA-1a, the compound of formula CA-1b, the compound of formula CA-1c, the compound of formula FA-1a, the compound of formula FA-1b, the compound of formula FA-1c, the compound of formula IA-1a, the compound of formula IA-1b and the compound of formula IA-1 c.
Test example 2
The method for evaluating the activity of the liver cancer in vitro comprises the following steps:
1. Cell lines and cell cultures
Human hepatoma cell line Hep G2 cells were derived from institute of biochemistry and cell biology (Shanghai, china) of academy of sciences of China, all cells were cultured under aseptic conditions, resuspended in DMEM containing 10% FBS and 1% penicillin/streptomycin amphotericin B mixture, cells were continuously cultured in incubator (HERACELL VIOS i, thermo Fisher) at 5% CO 2 and 37 ℃, and cells were passaged 1 time for 3 days using trypsin to maintain logarithmic cell growth.
2. CCK-8 experiment
The invention detects that the compound (the compound shown in the formula CA, the compound shown in the formula FA, the compound shown in the formula IA and the compound prepared in examples 1-9) is cytotoxic to liver cancer Hep G2 cells through CCK-8 assay. The Hep G2 cells of the logarithmic growth cycle were taken for the experiment. Cells were diluted to 5X 10 4 cells/mL with DMEM, and 96-well plates were seeded with a cell fluid volume of 100. Mu.L per well, followed by 12 h in a 5% CO 2 and 37℃incubator. Subsequently, different concentrations (0, 3.15, 6.25, 12.5, 25, 50, 100. Mu.M) of the above test compounds were added to 96-well plates at 25. Mu.L per well, and incubation was continued for 48 h.10% CCK8 reagent was added to 96 well plates at 10. Mu.L per well for incubation 2h. The control group was treated in the same manner. The data on the plate were read using a full-wavelength microplate reader (Thermo ScientificTM Multiskan GO) at 450: 450 nm wavelength, cell viability (%) = 1- (OD control cells-OD treated cells)/OD control cells x 100%.
3. Data analysis
The data for each experimental step was analyzed using GRAPHPAD PRISM software (version 8.3). All experimental data are expressed as mean ± SD. Group comparisons used paired sample t-test and one-way analysis of variance (ANOVA). Each experiment was performed at least three times. Results are marked as significant when p <0.05, and as significant when p < 0.01.
The method is used for detecting the anti-tumor activity and cytotoxicity of cinnamic acid and derivative compounds thereof, ferulic acid and derivative compounds thereof, indole-3-acetic acid and derivative compounds thereof, and the results are shown in figures 19-21. According to the graph 19-21, the compound of the formula CA-1a and the compound of the formula FA-1a provided by the invention can inhibit the survival rate of a liver cancer cell line, the compound of the formula IA-1a can inhibit the survival rate of the liver cancer cell line at 50 mu M, the compound of the formula CA-1b and the compound of the formula CA-1c have lower cytotoxicity to Hep G2, the compound of the formula FA-1b, the compound of the formula FA-1c, the compound of the formula IA-1b and the compound of the formula IA-1c have no toxicity to Hep G2 cells, and the mother nucleus compounds CA, FA and IA have no toxicity to Hep G2 cells.
The above examples show that the compound provided by the invention has anti-inflammatory and anti-tumor effects, and can be used as a medicament for treating liver cancer to improve the anti-cancer effect.
Although the foregoing embodiments have been described in some, but not all embodiments of the invention, other embodiments may be obtained according to the present embodiments without departing from the scope of the invention.
Claims (10)
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
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| WO1998031688A1 (en) * | 1997-01-20 | 1998-07-23 | Adir Et Compagnie | Novel boronic acid derivatives inhibitors of angiogenesis |
| CN107602462A (en) * | 2017-10-10 | 2018-01-19 | 浦拉司科技（上海）有限责任公司 | The method that one kind prepares hydroxyl 2 (1H) quinolinone |
| CN114751927A (en) * | 2022-03-08 | 2022-07-15 | 中山大学 | Boric acid compound, preparation method and application |
| CN117402183A (en) * | 2022-07-13 | 2024-01-16 | 正大天晴药业集团股份有限公司 | Boron-containing compounds and their medicinal uses |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1998031688A1 (en) * | 1997-01-20 | 1998-07-23 | Adir Et Compagnie | Novel boronic acid derivatives inhibitors of angiogenesis |
| CN107602462A (en) * | 2017-10-10 | 2018-01-19 | 浦拉司科技（上海）有限责任公司 | The method that one kind prepares hydroxyl 2 (1H) quinolinone |
| CN114751927A (en) * | 2022-03-08 | 2022-07-15 | 中山大学 | Boric acid compound, preparation method and application |
| CN117402183A (en) * | 2022-07-13 | 2024-01-16 | 正大天晴药业集团股份有限公司 | Boron-containing compounds and their medicinal uses |
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| "RN：3056-73-3等", STN REGISTRT, 16 May 2019 (2019-05-16), pages 1 - 4 * |
| "RN：73031-14-8，52190-18-8", STN REGISTRT, 16 November 1984 (1984-11-16), pages 1 - 2 * |
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