Flavanone ring-opened amide derivatives, and preparation method and application thereof

Abstract

The application belongs to the technical field of pharmaceutical chemistry and pharmacology, and particularly relates to a flavanone ring-fused amide derivative, a preparation method and application thereof. A structural formula of the flavanone ring-fused amide derivative is shown in the following formula: wherein R represents one of a phenyl group, a 4-fluorophenyl group, a 4-bromophenyl group, a 2-iodophenyl group, a 2-bromophenyl group, a benzyl group, a 4-chlorobenzyl group, a 4-bromobenzyl group, a 4-fluorobenzyl group and a propargyl group. The flavanone ring-fused amide derivative is a flavanone ring-fused amide compound, and pharmacological research shows that the compound has strong breast cancer cell proliferation inhibition activity, and can be applied to preparation of a drug for preventing and treating breast cancer.

Description

Technical Field

[0001] This invention belongs to the fields of medicinal chemistry and pharmacology, specifically relating to a flavanone schizoamide derivative, its preparation method, and its application. Background Technology

[0002] Natural products, due to their unique chemical structures and broad biological activities, have always been an important source for the discovery of lead compounds for anti-tumor drugs. Among them, plant-derived active ingredients play a pivotal role in new drug development.

[0003] Flavanones are an important subclass of the flavonoid family, with a basic structure consisting of a dihydroflavonoid skeleton. These compounds are widely distributed in nature, especially abundant in fruits of the genus *Citrus* (Rutaceae family). Flavanones possess broad and significant biological activities, with their mechanisms of action primarily based on scavenging free radicals and activating antioxidant pathways such as NrF2. They also effectively inhibit inflammatory mediators, exhibiting potent antioxidant and anti-inflammatory activities.

[0004] However, natural flavanones have certain structural limitations. The specific substitution patterns of their parent core structure limit further enhancement of activity to some extent, and the influence of the type, position, and number of different substituents on activity is not yet fully elucidated. In addition, the active compounds reported in existing studies are mostly concentrated in a few known structures from natural sources, resulting in a relatively narrow chemical space, which makes it difficult to meet the structural diversity requirements for different tumor targets and mechanisms of action.

[0005] Therefore, designing and synthesizing novel flavanone compounds and exploring their antitumor activity is of great research significance for enriching the structural diversity of this class of compounds and discovering antitumor lead molecules with development potential. Summary of the Invention

[0006] In view of this, the purpose of the present invention is to provide a flavanone schizoamide derivative, its preparation method and application, wherein the flavanone schizoamide derivative has strong inhibitory activity against breast cancer cell proliferation and can be used in the preparation of drugs for the prevention and treatment of breast cancer.

[0007] In a first aspect, the present invention provides a flavanone schizoamide derivative having the structure shown in the following formula:

[0008] ,

[0009] Wherein, R represents one of phenyl, 4-fluorophenyl, 4-bromophenyl, 2-iodophenyl, 2-bromophenyl, benzyl, 4-chlorobenzyl, 4-bromobenzyl, 4-fluorobenzyl, and propynyl.

[0010] In some embodiments of the present invention, the flavanone cleavage amide derivatives have structures as shown in any one of formulas 3a-3d:

[0011]

[0012] in,

[0013] When R is phenyl, the flavanone cleavage amide derivative is a compound with the structure shown in formula 3a;

[0014] When R is 2-iodophenyl, the flavanone schizoamide derivative is a compound with the structure shown in formula 3b;

[0015] When R is benzyl, the flavanone cleavage amide derivative is a compound with the structure shown in formula 3c;

[0016] When R is a propynyl group, the flavanone schizoamide derivative is a compound with the structure shown in formula 3d.

[0017] A second aspect of the present invention provides a method for preparing flavanone cleavage amide derivatives, comprising the following steps:

[0018] S1. A flavanone ring-expanded derivative 1 was obtained by reacting flavanone with m-chloroperoxybenzoic acid and sodium bicarbonate in dichloromethane;

[0019] S2. Ester hydrolysis derivative 2 was obtained by reacting flavanone ring-expanding derivative 1 with sodium hydroxide solution in methanol;

[0020] S3. A flavanone schizoamide derivative 3 was obtained by reacting ester hydrolysis derivative 2 with RNH2, 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate, and N,N-diisopropylethylamine in dichloromethane.

[0021] The reaction formula for the above preparation method is as follows:

[0022] ,

[0023] Wherein, R represents one of phenyl, 4-fluorophenyl, 4-bromophenyl, 2-iodophenyl, 2-bromophenyl, benzyl, 4-chlorobenzyl, 4-bromobenzyl, 4-fluorobenzyl, and propynyl.

[0024] In some embodiments of the present invention, the above-described preparation method includes the following steps:

[0025] (1) Dissolve flavanone, m-chloroperoxybenzoic acid and sodium bicarbonate in dichloromethane to obtain the first reaction solution. Add deionized water to the first reaction solution to quench the reaction, extract with ethyl acetate, collect the organic phase and wash it successively with water, saturated brine, dry with anhydrous MgSO4, concentrate under reduced pressure, and then column chromatography to obtain a pale yellow solid, namely flavanone ring-expanded derivative 1.

[0026] In some embodiments of the present invention, in step S1 of the above preparation method, the molar ratio of flavanone, m-chloroperoxybenzoic acid and sodium bicarbonate is 1:1.5:2.

[0027] In some embodiments of the present invention, in step S1 of the above preparation method, the reaction temperature is 0℃-40℃ and the reaction time is 12-24 hours.

[0028] (2) Dissolve flavanone ring-expanding derivative 1 in methanol, add sodium hydroxide aqueous solution to obtain the second reaction solution. Add the first reaction solution to 2M hydrochloric acid aqueous solution, extract with ethyl acetate, collect the organic phase and wash successively with water, saturated brine, dry with anhydrous MgSO4, concentrate under reduced pressure, and then column chromatography to obtain a white solid, namely ester hydrolysis derivative 2.

[0029] In some embodiments of the present invention, in step S2 of the above preparation method, the molar ratio of flavanone ring-expanding derivative 1 to sodium hydroxide is 1:5.

[0030] In some embodiments of the present invention, in step S2 of the above preparation method, the reaction temperature is 0℃-50℃ and the reaction time is 12-24 hours.

[0031] (3) Ester hydrolysis derivative 2, RNH2, 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate and N,N-diisopropylethylamine were dissolved in dichloromethane to obtain the third reaction solution. The reaction was quenched with deionized water, extracted with ethyl acetate, and the organic phase was collected and washed successively with water, saturated brine, dried over anhydrous MgSO4, concentrated under reduced pressure, and then subjected to column chromatography to obtain a white solid, namely flavanone schizoamide derivative 3.

[0032] In some embodiments of the present invention, in step S3 of the above preparation method, the molar ratio of ester hydrolysis derivative 2, amine, 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate and N,N-diisopropylethylamine is 1:1.5:2:4.

[0033] In some embodiments of the present invention, in step S3 of the above preparation method, the reaction temperature is 0℃-40℃ and the reaction time is 12-24 hours.

[0034] In a third aspect, the present invention provides the use of the above-mentioned flavanone schizoamide derivatives in the preparation of a medicament for treating cancer, wherein the cancer is breast cancer.

[0035] Compared with the prior art, the present invention provides a flavanone schizoamide derivative, its preparation method and application. The flavanone schizoamide derivative is a compound obtained by schizosynthesis of flavanone skeleton. Pharmacological studies have shown that this type of compound has strong inhibitory activity against breast cancer cell proliferation and can be used in the preparation of drugs for the prevention and treatment of breast cancer. Detailed Implementation

[0036] The technical solutions in the embodiments of the present invention will be clearly and completely described below. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0037] Example 1

[0038] Under a nitrogen atmosphere, flavanone (1.0 mmol) was dissolved in a dry dichloromethane solution, and m-chloroperoxybenzoic acid (1.5 mmol) and sodium bicarbonate (2.0 mmol) were added to the reaction mixture. The reaction mixture was stirred at room temperature for 24 hours. After the reaction was completed as monitored by thin-layer chromatography, the mixture was added to deionized water and extracted with ethyl acetate. The organic phase was collected, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was separated by column chromatography (petroleum ether:ethyl acetate = 45:1). A white solid flavanone ring-expanded derivative 1 was given. 1 H NMR (400 MHz, CDCl3) δ 7.38 (s, 5H, ArH),), 7.19-7.12 (m, 3H,ArH),), 7.06-6.98 (m, 1H, ArH),), 5.71 (dd, J = 7.3, 5.8 Hz, 1H,-CH-), 3.11(qd, J = 13.3, 6.6 Hz, 2H,-CH2-); 13 C NMR (100 MHz, CDCl3) δ 167.6, 145.7,145.2, 138.6, 129.1, 128.8, 126.6, 126.2, 125.8, 124.3, 120.4, 83.5, 38.5.HRMS (ESI): m / z calcd for C 15 H 12 O3Na: 263.0687; found: 263.0684 [M+Na]+ .

[0039] Example 2

[0040] The flavanone ring-expanding derivative 1 (1.0 mmol) was dissolved in methanol, and a sodium hydroxide (5.0 mmol) aqueous solution was added dropwise. The reaction mixture was stirred at room temperature for 12 h. After the reaction was completed as monitored by thin-layer chromatography, the pH was adjusted to 1 with 3M HCl, and deionized water was added to the reaction mixture. The mixture was extracted with ethyl acetate, and the organic phase was collected and washed with saturated sodium bicarbonate. After drying with anhydrous sodium sulfate, the mixture was concentrated under reduced pressure, and the crude product was separated by column chromatography (petroleum ether: ethyl acetate = 2:1). A white solid ester hydrolysis derivative 2 was obtained. 1 H NMR (400 MHz, DMSO-d6) δ 12.40 (s, 1H,-COOH), 9.00 (s, 1H,-OH), 7.50-7.42 (m, 2H, ArH), 7.35-7.21 (m, 3H, ArH), 6.81-6.64 (m, 3H, ArH), 6.56(td, J = 7.6, 1.7 Hz, 1H, ArH), 5.65 (dd, J = 9.0, 4.4 Hz, 1H,-CH-), 3.00(dd, J = 16.1, 9.0 Hz, 1H,-CH2-), 2.76 (dd, J = 16.1, 4.4 Hz, 1H,-CH2-). 13 CNMR (100 MHz, DMSO-d6) δ 172.3, 147.9, 145.5, 141.0, 128.8, 128.3, 127.0,122.1, 119.3, 116.5, 76.9, 43.2. HRMS (ESI): m / z calcd for C 15 H 14 O4Na:281.0795; found: 281.0790 [M+Na] + .

[0041] Example 3

[0042] Under a nitrogen atmosphere, ester hydrolysis derivative 2 (1.0 mmol), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (2.0 mmol), and N,N-diisopropylethylamine (4.0 mmol) were dissolved in a dry dichloromethane solution, and the mixture was stirred at room temperature for 1.5 h. Aniline (1.5 mmol) was then added to the reaction solution, and stirring was continued at this temperature for another 24 h. After the reaction was monitored by thin-layer chromatography, the mixture was concentrated under reduced pressure, and the crude product was separated by column chromatography. A white solid flavanone schizoamide derivative 3a was obtained in 82% yield. 1 H NMR (400 MHz, CDCl3) δ 7.55-7.50 (m, 2H,ArH), 7.40-.29 (m, 7H, ArH), 7.14 (d, J = 7.4 Hz, 1H, ArH), 6.97-6.87 (m, 2H,ArH), 6.57-6.46 (m, 2H, ArH), 5.37 (dd, J = 10.0, 2.7 Hz, 1H,-CH-), 3.17 (dd,J = 16.0, 10.0 Hz, 1H,-CH2-), 2.84 (dd, J = 16.0, 2.7 Hz, 1H,-CH2-); 13 C NMR(100 MHz, CDCl3) δ 169.4, 149.2, 139.8, 137.2, 129.1, 128.8, 128.6, 126.8,124.6, 120.8, 120.3, 119.3, 116.6, 79.8, 38.7. HRMS (ESI): m / z calcd forC 21 H 19 NO3Na: 356.1267; found: 356.1263 [M+Na] + .

[0043] Example 4

[0044] Under a nitrogen atmosphere, flavanone ring-expanding derivative 2 (1.0 mmol), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (2.0 mmol), and N,N-diisopropylethylamine (4.0 mmol) were dissolved in a dry dichloromethane solution, and the mixture was stirred at room temperature for 1.5 h. Then, 2-iodoaniline (1.5 mmol) was added to the reaction mixture, and stirring was continued at this temperature for another 24 h. After the reaction was monitored by thin-layer chromatography, the mixture was concentrated under reduced pressure, and the crude product was separated by column chromatography. A white solid flavanone schizoamide derivative 3b was obtained, with a yield of 71%.1 H NMR (400 MHz, CDCl3) δ 7.55-7.50(m, 2H, ArH), 7.39-7.29 (m, 7H, ArH), 6.97-6.86 (m, 2H, ArH), 6.56-6.44 (m,2H, ArH), 5.37 (dd, J = 10.0, 2.7 Hz, 1H,-CH-), 3.17 (dd, J = 16.0, 10.0 Hz,1H,-CH2-), 2.84 (dd, J = 16.0, 2.7 Hz, 1H,-CH2-); 13 C NMR (100 MHz, CDCl3) δ169.4, 149.2, 139.8, 137.2, 129.1, 128.8, 128.6, 126.8, 120.8, 120.3, 119.3,116.6, 79.8, 38.7. HRMS (ESI): m / z calcd for C 21 H 18 O3NaI: 482.0228; found:482.0229 [M+Na] + .

[0045] Example 5

[0046] Under a nitrogen atmosphere, flavanone ring-expanding derivative 2 (1.0 mmol), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (2.0 mmol), and N,N-diisopropylethylamine (4.0 mmol) were dissolved in a dry dichloromethane solution, and the mixture was stirred at room temperature for 1.5 h. Benzylamine (1.5 mmol) was then added to the reaction mixture, and stirring was continued at this temperature for another 24 h. After the reaction was monitored by thin-layer chromatography, the mixture was concentrated under reduced pressure, and the crude product was separated by column chromatography. A white solid flavanone schizoamide derivative 3c was obtained, with a yield of 77%. 1H NMR (400 MHz, Chloroform-d) δ 8.72(s, 1H,-NH-), 7.37-7.29 (m, 7H, ArH), 7.27 – 7.22 (m, 3H, ArH), 6.92 (dtd, J= 15.2, 8.1, 1.8 Hz, 2H, ArH), 6.56-6.41 (m, 2H, ArH), 5.32 (dd, J = 10.0,2.8 Hz, 1H,-CH-), 4.50 (d, J = 5.6 Hz, 2H-N-CH2-), 3.11-2.87 (m, 1H,-CH2-), 2.69 (dd, J = 16.0, 2.8 Hz, 1H,-CH2-); 13 C NMR (100 MHz, CDCl3) δ 170.9,149.7, 144.4, 139.9, 137.5, 128.8, 128.7, 128.5, 128.0, 127.8, 126.9, 124.8,121.4, 119.2, 116.8, 80.1, 44.0, 43.7. HRMS (ESI): m / z calcd for C 22 H 21 NO3Na:370.1432; found: 370.1419 [M+Na] + .

[0047] Example 6

[0048] Under a nitrogen atmosphere, flavanone ring-expanding derivative 2 (1.0 mmol), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (2.0 mmol), and N,N-diisopropylethylamine (4.0 mmol) were dissolved in a dry dichloromethane solution, and the mixture was stirred at room temperature for 1.5 h. Propyleneamine (1.5 mmol) was then added to the reaction mixture, and stirring was continued at this temperature for another 24 h. After the reaction was monitored by thin-layer chromatography, the mixture was concentrated under reduced pressure, and the crude product was separated by column chromatography. A white solid flavanone schizoamide derivative 3d was obtained, with a yield of 69%. 1H NMR (400 MHz, CDCl3) δ 8.45 (s, 1H,-NH-), 7.36 (d, J = 4.1 Hz, 5H, ArH), 6.98-6.83 (m, 2H, ArH), 6.56-6.38 (m,2H, ArH), 5.28 (dd, J = 10.3, 2.7 Hz, 1H,-CH-), 3.15 (s, 1H,-C-CH-,), 3.06-2.93 (m, 2H, -N-CH2-), 2.67 (dd, J = 16.1, 2.7 Hz, 1H,-CH2-), 2.25 (t, J = 2.6Hz, 1H, -CH2-); 13 C NMR (100 MHz, CDCl3) δ 170.8, 149.4, 144.4, 139.8, 128.7,128.6, 126.8, 124.7, 121.2, 119.2, 116.7, 79.9, 72.2, 43.5, 29.5. HRMS (ESI):m / z calcd for C 18 H 17 NO3Na: 318.1109; found: 318.1106 [M+Na] + .

[0049] To better understand the essence of this invention, the following pharmacological experimental results demonstrating the inhibitory effect of the flavanone schizoamide derivatives provided by this invention on the growth of mouse breast cancer cells (4T1) illustrate its novel application in the field of antitumor drug research. The pharmacological examples provide partial activity data for representative compounds. It must be noted that the pharmacological examples of this invention are for illustrative purposes only and not for limiting the invention. Simple modifications made to this invention based on its essence are all within the scope of protection claimed by this invention.

[0050] Drug Experiment Example 1

[0051] Cytotoxic activity of compounds 3a-3d and paclitaxel against mouse breast cancer cells (4T1)

[0052] Mouse breast cancer cells (4T1) were cultured in RPMI-1640 complete medium containing 10% fetal bovine serum, 100 U / mL penicillin and 100 U / mL streptomycin at 37°C in a humidified air incubator containing 5% CO2.

[0053] Cells in the logarithmic growth phase were collected and spaced at 5 × 10⁶ cells per well. 3Cells were seeded at a density of [number] cells per well in 96-well plates and cultured for 24 hours to allow for full cell adhesion. The test compound was dissolved in DMSO to prepare 1×10 [units of solution]. -2 The stock solution was diluted with complete culture medium to the corresponding concentrations to obtain solutions of the test compound at different concentrations. After removing the original culture medium, culture medium containing different concentrations of compound 3a was added, with four parallel wells for each concentration, and the mixture was incubated for 68 hours. After incubation, tetramethylazobium salt (MTT) solution was added to each well, and the mixture was incubated for another 4 hours. The culture medium was then discarded, and 150 μL of dimethyl sulfoxide was added to each well, followed by shaking for 10 min. Finally, the absorbance (A) at 570 nm was measured using a microplate reader, and the half-maximal inhibitory concentration (IC50) was calculated. 50 ), as shown in Table 1.

[0054] Table 1. Results of cytotoxic activity tests of compounds 3a-3d and paclitaxel.

[0055]

[0056] As shown in Table 1, the flavanone schizoamide derivatives provided by this invention possess significant biological activity. In vitro cytotoxicity assays on mouse breast cancer cells (4T1) demonstrate that these flavanone schizoamide derivatives inhibit tumor cell growth and have the potential to be developed into novel anti-tumor drugs. From the above pharmacological examples, we can see that these compounds exhibit strong cytotoxic activity against this tumor cell line, with most compounds showing cytotoxic activity close to that of the positive control paclitaxel, indicating their potential for development into anti-tumor drugs.

[0057] While some embodiments of the present general inventive concept have been shown and described, those skilled in the art will understand that changes may be made to these embodiments without departing from the principles and spirit of the present general inventive concept, the scope of which is defined by the claims and their equivalents.

Claims

1. A flavanone schizoamide derivative, characterized in that, The structural formula of the flavanone cleavage amide derivative is shown below: ， Wherein, R represents one of phenyl, 4-fluorophenyl, 4-bromophenyl, 2-iodophenyl, 2-bromophenyl, benzyl, 4-chlorobenzyl, 4-bromobenzyl, 4-fluorobenzyl, and propynyl.

2. The flavanone schizoamide derivative according to claim 1, characterized in that, The flavanone cleavage amide derivatives have structures as shown in any one of formulas 3a-3b:

3. A method for preparing the flavanone cleavage amide derivative as described in claim 1, characterized in that, Includes the following steps: S1. A flavanone ring-expanded derivative 1 was obtained by reacting flavanone with m-chloroperoxybenzoic acid and sodium bicarbonate in dichloromethane; S2. Ester hydrolysis derivative 2 was obtained by reacting flavanone ring-expanding derivative 1 with sodium hydroxide solution in methanol; S3. The flavanone schizoamide derivative 3 was obtained by reacting ester hydrolysis derivative 2 with RNH2, 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate, and N,N-diisopropylethylamine in dichloromethane. The reaction formula for the above preparation method is as follows: Wherein, R represents one of phenyl, 4-fluorophenyl, 4-bromophenyl, 2-iodophenyl, 2-bromophenyl, benzyl, 4-chlorobenzyl, 4-bromobenzyl, 4-fluorobenzyl, and propynyl.

4. The preparation method according to claim 3, characterized in that, In step S1, the molar ratio of flavanone, m-chloroperoxybenzoic acid and sodium bicarbonate is 1:1.5:

2.

5. The preparation method according to claim 3, characterized in that, In step S1, the reaction temperature is 0℃-40℃ and the reaction time is 12-24 hours.

6. The preparation method according to claim 3, characterized in that, In step S2, the molar ratio of flavanone ring-expanding derivative 1 to sodium hydroxide is 1:

5.

7. The preparation method according to claim 3, characterized in that, In step S2, the reaction temperature is 0℃-50℃ and the reaction time is 12-24 hours.

8. The preparation method according to claim 3, characterized in that, In step S3, the molar ratio of ester hydrolysis derivative 2, RNH2, 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate and N,N-diisopropylethylamine is 1:1.5:2:

4.

9. The preparation method according to claim 3, characterized in that, In step S3, the reaction temperature is 0℃-40℃ and the reaction time is 12-24 hours.

10. The use of the flavanone schizoamide derivative as described in claim 1 in the preparation of a medicament for treating cancer, wherein the cancer is breast cancer.

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