Flavanone schmidt rearrangement derivative, 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 schmidt rearrangement derivative, a preparation method and application thereof. A structural formula of the flavanone schmidt rearrangement derivative is shown in the following formula: wherein R represents one of benzyl, propynyl, allyl, isopentenyl, methyl, ethyl, isopropyl and n-butyl. The flavanone schmidt rearrangement derivative is a rearrangement compound obtained by schmidt rearrangement reaction of flavanone, and a derivative obtained by further alkylation. Pharmacological research shows that the compound has strong liver cancer cell proliferation inhibition activity, and can be applied to preparation of a drug for preventing and treating liver cancer.

Description

Technical Field

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

[0002] Cancer is a major public health problem that seriously endangers human health, and the discovery and research of anti-tumor components from plants is one of the core directions in this field.

[0003] Flavanones are natural flavonoids widely found in citrus fruits and various medicinal plants. Modern pharmacological studies have confirmed that flavanones possess a variety of biological activities, including antioxidant, anti-inflammatory, antibacterial, and antiviral effects, making them a research hotspot in drug development (Toxicol Res. 2021, 37, 147-162). Their mechanisms of action mainly involve scavenging free radicals, activating antioxidant signaling pathways such as nuclear factor E2-related factor 2 (Nrf2), and effectively inhibiting the production and release of inflammatory mediators, exhibiting significant antioxidant and anti-inflammatory activities. Furthermore, studies have shown that flavanones have potential applications in cardiovascular and neuroprotective fields.

[0004] However, the poor water solubility, rapid metabolism, and poor stability of flavanones limit their biological activity and clinical applications to some extent. Despite these structural limitations, their biological activity can still be enhanced or derivatives with novel functions can be developed through rational structural modification and biotransformation strategies. Therefore, designing and synthesizing novel flavanone compounds and systematically evaluating their antitumor activity is of significant scientific importance and application potential for enriching the structural diversity of this class of compounds and discovering potential antitumor lead molecules (Mol Divers, 2026, 30, 373-382).

[0005] Therefore, in order to overcome the inherent structural limitations of flavanone compounds and their deficiencies such as insufficient biological activity and solubility, it is urgent to optimize them through structural modification strategies in order to obtain novel derivatives with synergistic enhancement of activity and drug-like properties. Summary of the Invention

[0006] In view of this, the purpose of the present invention is to provide a flavanone Schmidt rearrangement derivative, its preparation method and application. The flavanone Schmidt rearrangement derivative is a rearranged compound obtained by flavanone through Schmidt rearrangement reaction, and further alkylated to obtain a derivative. Pharmacological studies have shown that this type of compound has strong inhibitory activity against the proliferation of liver cancer cells and can be used in the preparation of drugs for the prevention and treatment of liver cancer.

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

[0008] ,

[0009] Wherein, R represents one of benzyl, propynyl, allyl, isopentenyl, methyl, ethyl, isopropyl, and n-butyl.

[0010] In some embodiments of the present invention, the flavanone Schmidt rearrangement derivatives have structures as shown in any one of formulas 2a-2d:

[0011]

[0012] in,

[0013] When R is benzyl, the flavanone Schmidt rearrangement derivative is a compound with the structure shown in formula 2a;

[0014] When R is a propynyl group, the flavanone Schmidt rearrangement derivative is a compound with the structure shown in formula 2b;

[0015] When R is allyl, the flavanone Schmidt rearrangement derivative is a compound with the structure shown in formula 2c;

[0016] When R is isopentenyl, the flavanone Schmidt rearrangement derivative is a compound with the structure shown in formula 2d.

[0017] A second aspect of the present invention provides a method for preparing a flavanone Schmidt rearrangement derivative, comprising the following steps:

[0018] S1. The Schmidt rearrangement intermediate 1 of flavanone was obtained by reacting flavanone with sodium azide in trifluoroacetic acid.

[0019] S2. Schmidt rearrangement intermediate 1 reacts with a bromoalkane in the presence of sodium hydride in tetrahydrofuran to give the corresponding flavanone Schmidt rearrangement derivative 2.

[0020] The reaction formula for the above preparation method is as follows:

[0021] ,

[0022] Wherein, R represents one of benzyl, propynyl, allyl, isopentenyl, methyl, ethyl, isopropyl, and n-butyl.

[0023] In some embodiments of the present invention, the above-described preparation method includes the following steps:

[0024] (1) Dissolve flavanone and sodium azide in trifluoroacetic acid and react to obtain the first reaction solution. Concentrate the first reaction solution under reduced pressure, add saturated sodium bicarbonate 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 flavanone Schmidt rearrangement intermediate 1.

[0025] In some embodiments of the present invention, in step S1 of the above preparation method, the molar ratio of flavanone and sodium azide is 1:5.

[0026] In some embodiments of the present invention, in step S1 of the above preparation method, the reaction temperature is 0℃-50℃ and the reaction time is 12-24 hours.

[0027] (2) The flavanone Schmidt rearrangement intermediate 1 was dissolved in tetrahydrofuran, and sodium hydride was added in portions under ice bath conditions. Then, a tetrahydrofuran solution of a bromoalkane was slowly added dropwise to carry out the reaction, yielding a second reaction solution. The second reaction solution was added to a 2M hydrochloric acid aqueous solution, 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 the flavanone Schmidt rearrangement derivative 2.

[0028] In some embodiments of the present invention, in step S2 of the above preparation method, the molar ratio of flavanone Schmidt rearrangement intermediate 1 to bromoalkane and sodium hydride is 1:1.5:2.

[0029] 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.

[0030] In a third aspect, the present invention provides the use of the above-mentioned flavanone Schmidt rearrangement derivative in the preparation of a medicament for treating cancer, wherein the cancer is liver cancer.

[0031] Compared with the prior art, the present invention provides a flavanone Schmidt rearrangement derivative, its preparation method and application. The flavanone Schmidt rearrangement derivative is a rearranged compound obtained by flavanone through Schmidt rearrangement reaction, and further alkylated to obtain a derivative. Pharmacological studies have shown that this type of compound has strong inhibitory activity against the proliferation of liver cancer cells and can be applied to the preparation of drugs for the prevention and treatment of liver cancer. Detailed Implementation

[0032] 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.

[0033] Example 1

[0034] Under nitrogen protection, flavanone (1.0 mmol) was dissolved in trifluoroacetic acid, and sodium azide (5.0 mmol) was added in portions. The reaction mixture was stirred overnight at room temperature. After the reaction was complete, the mixture was concentrated under reduced pressure, quenched with saturated sodium bicarbonate, and extracted with a large amount of water and 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 to give a white solid 1 in 68% yield. 1 H NMR (400 MHz, CDCl3) δ 8.45 (dd, J =8.0, 1.7 Hz, 1H, ArH), 7.65-7.55 (m, 3H, ArH), 7.50-7.41 (m, 3H, ArH), 7.36-7.30 (m, 1H, ArH), 7.23 (dd, J = 8.3, 1.1 Hz, 1H, ArH), 5.61 (t, J=5.5 Hz,1H,-CH-), 5.19-5.11 (m, 2H,-CH2-); 13 C NMR (100 MHz, CDCl3) δ 156.9, 152.0,136.3, 133.4, 130.4, 129.3, 129.2, 126.1, 124.1, 121.6, 112.9, 79.0, 56.3; HRMS (ESI): m / z calcd for C 15 H 14 NO2: 240.1028; found: 240.1025 [M+H] + .

[0035] Example 2

[0036] Under nitrogen protection, 1 (1.0 mmol) was dissolved in anhydrous tetrahydrofuran. The reaction temperature was cooled to 0 °C, and NaH (2.0 mmol) was added. The reaction solution was stirred at this temperature for 30 minutes, and then benzyl bromide (1.2 mmol) was added. The reaction temperature was then raised to room temperature and stirred overnight. After the reaction was completed as monitored by thin-layer chromatography, the reaction was quenched with saturated ammonium chloride aqueous solution, and a large amount of water was added and the mixture was extracted with ethyl acetate. The organic phase was collected, washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was separated by column chromatography to give a white solid 2a in 51% yield. 1H NMR (400 MHz, CDCl3) δ 7.60-7.53 (m, 2H,ArH), 7.44 (d, J = 14.4 Hz, 1H, -CH-), 7.40-7.28 (m, 6H, ArH), 7.26-7.19 (m,2H,-CH2-), 7.17 (d, J = 4.5 Hz, 6H, ArH), 5.08 (s, 2H,-CH2-); 13 C NMR (100MHz, CDCl3) δ 156.2, 151.6, 135.5, 133.5, 133.4, 132.3, 129.1, 128.9, 128.6,128.3, 127.3, 127.0, 125.2, 121.7, 119.6, 113.1, 113.0, 70.9. HRMS (ESI): m / zcalcd for C 22 H 20 NO2: 330.1497; found: 330.1494 [M+H] + .

[0037] Example 3

[0038] Under nitrogen protection, 1 (1.0 mmol) was dissolved in anhydrous tetrahydrofuran solution. The reaction temperature was cooled to 0 °C, and NaH (2.0 mmol) was added. The reaction solution was stirred at this temperature for 30 minutes, and then bromopropyne (1.2 mmol) was added. The reaction temperature was then raised to room temperature and stirred overnight. After the reaction was monitored by thin-layer chromatography, the reaction was quenched with saturated ammonium chloride aqueous solution, and a large amount of water was added and extracted with ethyl acetate. The organic phase was collected, washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was separated by column chromatography to give a white solid 2b in 41% yield. 1 H NMR (400 MHz, CDCl3) δ 7.65-7.59 (m, 2H,ArH), 7.54 (d, J = 14.3 Hz, 1H, ArH), 7.46-7.42 (m, 2H, ArH), 7.37-7.30 (m,4H, ArH), 7.28-7.19 (m, 3H, -CH-, -CH2-), 4.74 (d, J = 2.4 Hz, 2H,-CH2-), 2.47(t, J = 2.4 Hz, 1H, -CH); 13C NMR (100 MHz, CDCl3) δ 154.5, 151.3, 133.5,133.3, 132.4, 129.1, 128.8, 127.1, 125.3, 122.3, 119.5, 113.2, 112.9, 60.4,55.9; HRMS (ESI): m / z calcd for C 18 H 16 NO2:278.1186; found: 278.1181 [M+H] + .

[0039] Example 4

[0040] Under nitrogen protection, 1 (1.0 mmol) was dissolved in anhydrous tetrahydrofuran solution. The reaction temperature was cooled to 0 °C, and NaH (2.0 mmol) was added. The reaction solution was stirred at this temperature for 30 minutes, and then 3-bromopropene (1.2 mmol) was added. The reaction temperature was then raised to room temperature and stirred overnight. After the reaction was monitored by thin-layer chromatography, the reaction was quenched with saturated ammonium chloride aqueous solution, and a large amount of water was added and the mixture was extracted with ethyl acetate. The organic phase was collected, washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was separated by column chromatography to give a white solid 2c in 67% yield. 1 H NMR (400 MHz, CDCl3) δ 7.84 (dd, J =7.7, 1.8 Hz, 1H, ArH), 7.52-7.33 (m, 7H, ArH), 7.21 (td, J = 7.6, 1.1 Hz, 1H,ArH), 7.04 (dd, J = 8.1, 1.0 Hz, 1H,-O-CH-), 5.75 (tdd, J = 12.1, 6.0, 4.4Hz, 1H,-CH=CH2), 5.48 (t, J = 5.0 Hz, 1H,-CH=CH2), 5.20-5.04 (m, 2H,-CH2-),4.46 (ddt, J = 15.2, 5.3, 1.6 Hz, 1H,-CH=CH2), 3.64 (d, J = 5.0 Hz, 2H,-CH2-); 13C NMR (100 MHz, CDCl3) δ 168.4, 153.7, 139.0, 132.9, 132.8, 130.9, 128.7,128.5, 127.8, 126.1, 124.0, 122.4, 118.1, 85.5, 51.0, 50.3; HRMS (ESI): m / zcalcd for C 18 H 18 NO2: 280.1342; found: 280.1338 [M+H] + .

[0041] Example 5

[0042] Under nitrogen protection, 1 (1.0 mmol) was dissolved in anhydrous tetrahydrofuran solution. The reaction temperature was cooled to 0 °C, and NaH (2.0 mmol) was added. The reaction solution was stirred at this temperature for 30 minutes, and then bromoisoprene (1.2 mmol) was added. The reaction temperature was then raised to room temperature and stirred overnight. After the reaction was monitored by thin-layer chromatography, the reaction was quenched with saturated ammonium chloride aqueous solution, and a large amount of water was added and the mixture was extracted with ethyl acetate. The organic phase was collected, washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was separated by column chromatography. A white solid was given for 2 days, with a yield of 63%. 1 H NMR (400 MHz, CDCl3) δ 7.40 (td, J =3.5, 1.6 Hz, 2H, ArH), 7.40-7.31 (m, 5H, ArH), 7.17-7.10 (m, 1H, ArH), 7.03(dd, J = 8.1, 1.1 Hz, 1H, ArH), 5.46 (t, J = 4.8 Hz, 1H,-CH-), 5.25 (ddp, J =6.7, 5.6, 1.5 Hz, 1H,-CH=C-), 4.58-4.52 (m, 2H,-N-CH2-), 3.58 (d, J = 4.9 Hz,2H,-CH2-), 1.70 (s, 3H,-CH3-), 1.59 (s, 3H, -CH3-); 13 C NMR (100 MHz, CDCl3) δ168.4, 156.1, 138.7, 133.3, 130.9, 128.9, 128.7, 126.9, 126.1, 123.9, 122.2,119.9, 112.7, 85.8, 50.7, 44.7, 25.6, 18.1; HRMS (ESI): m / z calcd forC20 H 21 NO2Na: 330.1472 ; found: 330.1470 [M+Na] + .

[0043] To better understand the essence of this invention, the following pharmacological experimental results demonstrating the inhibitory effect of the flavanone Schmidt rearrangement derivatives provided by this invention on the growth of human hepatocellular carcinoma cells (HepG2) 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.

[0044] Drug Experiment Example 1

[0045] Cytotoxic activity of compounds 2a-2d and paclitaxel against human hepatocellular carcinoma cells (HepG2) was tested.

[0046] Human liver cancer cells (HepG2) 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.

[0047] Cells in the logarithmic growth phase were collected and spaced at 5 × 10⁶ cells per well. 3 Cells 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.

[0048] Table 1. Results of cytotoxic activity tests of compounds 2a-2d and paclitaxel.

[0049]

[0050] As shown in Table 1, the flavanone Schmidt rearrangement derivatives provided by this invention possess significant biological activity. In vitro cytotoxic activity assays against human hepatocellular carcinoma cells (HepG2) demonstrate that these flavanone Schmidt rearrangement 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 these tumor cells and have the potential to be developed into anti-tumor drugs.

[0051] 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 Schmidt rearrangement derivative, characterized in that, The structural formula of the flavanone Schmidt rearrangement derivative is shown below: ， Wherein, R represents one of benzyl, propynyl, allyl, isopentenyl, methyl, ethyl, isopropyl, and n-butyl.

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

3. A method for preparing the flavanone Schmidt rearrangement derivative as described in claim 1, characterized in that, Includes the following steps: S1. The Schmidt rearrangement intermediate 1 of flavanone was obtained by the Schmidt rearrangement reaction of flavanone and sodium azide in trifluoroacetic acid; S2. Schmidt rearrangement intermediate 1 and a bromoalkane undergo a substitution reaction in tetrahydrofuran in the presence of sodium hydride to give the corresponding flavanone Schmidt rearrangement derivative 2. The reaction formula for the above preparation method is as follows: ， Wherein, R represents one of benzyl, propynyl, allyl, isopentenyl, methyl, ethyl, isopropyl, and n-butyl.

4. The preparation method according to claim 3, characterized in that, In step S1, the molar ratio of flavanone to sodium azide is 1:

5.

5. The preparation method according to claim 3, characterized in that, In step S1, the reaction temperature is 0℃-50℃ 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 Schmidt rearrangement intermediate 1 to bromoalkane and sodium hydride is 1:1.5:

2.

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 use of the flavanone Schmidt rearrangement derivative as described in claim 1 in the preparation of a medicament for treating cancer, wherein the cancer is liver cancer.

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