CN104529810A - Preparation method and application of arctigenin derivatives - Google Patents

Abstract

In the present invention, arctigenin is used as a lead compound to modify the structure of arctigenin by chemical methods such as demethylation, acylation of oxygen atoms, aminomethylation, ammonolysis and hydrolysis of esters, and 15 structural derivatives of arctigenin are synthesized. compounds, 7 of which are new compounds. In the structural formula R, R'=O or R=NHR'', R'=OH or R=R'=OH, R ₁ =OCH ₃ or H, R ₂ =H or COCH ₃ or COC ₆ H ₅ or COCH ₂ CH ₂ COOH, R ₃ =H or CH ₂ NR ₁ 'R ₂ ', R ₄ =R ₅ =H or SO ₃ Na, R ₆ =OCH ₃ or H, R ₇ =OCH ₃ or H. The present invention relates to the preparation process of the above-mentioned derivatives and the research on their anti-tumor activity.

Description

Preparation method and application of arctigenin derivatives

technical field

The invention relates to a preparation method and application of arctigenin derivatives.

Background technique

Arctium is the dry and ripe fruit of Arctium lappa, a plant belonging to the genus Arctium in the Compositae family. Burdock Fructus has the effects of dispelling wind and cooling, clearing the lungs and clearing rash, detoxifying the throat, and clearing the intestines. disease. The main medicinal component of Arctium Fructus is arctiin. Our research results and foreign reports all indicate that arctiin exerts its medicinal effect by metabolizing into arctigenin in the gastrointestinal tract. However, arctigenin is a lignan compound with low water solubility and low bioavailability, which brings certain difficulties to the development of new anticancer drugs for arctigenin. Therefore, the present invention relates to the structural modification of the traditional Chinese medicine arctigenin as the lead compound and then the development of new drugs. It is expected to improve the water solubility of arctigenin, improve the bioavailability, and facilitate the dosage form, and to find safer, more effective, less toxic and convenient medication. New antitumor drugs.

Contents of the invention

The object of the present invention is to provide the preparation method of arctigenin derivative, and its general structural formula is formula (І), and formula (І) compound is to be that lead compound synthetically obtains with arctigen, through hydroxyl, aromatic ring, Lactone ring reaction sites for the synthesis of arctigenin derivatives.

(I)

Another object of the present invention is to provide the use of arctigenin derivatives and study their antitumor activity.

The technical solutions adopted are:

In the structural formula, R=NHR'', R'=OH, R ₁ =CH ₃ , R ₂ =R ₃ =R ₄ =R ₅ =H, R ₆ =R ₇ =CH ₃ , using chemical methods, through ammonia solution Methods The lactone ring of arctigenin was opened to obtain aminolysis derivatives.

In the structural formula, R, R'=O, R ₁ =R ₂ =R ₃ =R ₄ =R ₅ =H, R ₆ =CH ₃ or H, R ₇ =CH ₃ or H, the chemical method is used in the formula, the Arctigenin is converted to semidemethylated or perdemethylated derivatives.

In the structural formula R, R'=O, R ₁ =CH ₃ , R ₂ =H, R ₃ =CH ₂ NR ₁ 'R ₂ ', R ₄ =R ₅ =H, R ₆ =R ₇ =CH ₃ , using Chemically, by aminomethylation (Mannich reaction) into nitrogen-containing derivatives of arctigenin.

In the structural formula, R ₁ '=CH ₃ , CH ₂ CH ₃ , R ₂ '=CH ₃ , CH ₂ CH; or . Except for the nitrogen-containing derivatives of piperidine ring, the other compounds of this kind of compounds are all new compounds.

Although the nitrogen-containing derivative of the piperidine ring is a reported compound, the present invention uses glacial acetic acid as the solvent instead of nitrobenzene as the solvent reported in the literature to prepare the compound for the first time, which is easy to post-process, reduces economic costs, and has a simple and convenient preparation process.

In the structural formula, R, R'=O, R ₁ =CH ₃ , R ₂ =R ₃ =H, R ₄ =R ₅ =SO ₃ Na, R ₆ =R ₇ =CH ₃ , using chemical methods, through the aromatic ring sulfonylation of arctigenin into sulfonate derivatives.

In the structural formula, R, R'=O, R ₁ =CH ₃ , R ₂ =COCH ₃ or COC ₆ H ₅ or COCH ₂ CH ₂ COOH, R ₃ =R _{4 =R 5} =H, _{R 6 =} R ₇ =CH _3. In the formula, R ₂ is the side chain part of the hydroxyl group of the molecular formula of arctigenin, which is converted into fat-soluble derivatives or water-soluble derivatives of arctigenin through acylation of oxygen atoms by chemical methods. Compared with the reaction method in which triethylamine is used as the solvent and stirred overnight at room temperature in the literature, the reaction time is shortened, and methylene chloride is used as the solvent, the post-treatment is easy, the economic cost is reduced, and the process conditions are simplified.

In the structural formula, R=R'=OH, R ₁ =CH ₃ , R ₂ =R ₃ =R ₄ =R ₅ =H, R ₆ =R ₇ =CH ₃ , the arctiin The hydrolyzed derivatives of arctigenin are obtained after ring opening of the lactone ring of the element. Although this compound is a reported compound, the present invention adopts arctigenin alkali hydrolysis method to prepare this compound for the first time. This compound is more polar than arctigenin and can be used as a prodrug of arctigenin.

The preparation process of arctigenin ammonolysis derivatives: add arctigenin and monosubstituted primary amine solution into a round bottom flask, stir at room temperature, stop the reaction, and concentrate the reaction solution under reduced pressure, then prepare liquid phase separation or recrystallization to obtain the target compound.

The structural characteristics of the ammonolysis derivatives of arctigenin are R=NHR'', R''=CH ₂ CH ₂ CH ₃ , CH ₂ CH ₂ OH and CH ₂ C ₆ H ₅ , the substituted propylamine, ethanolamine and benzyl The ammonolysis reaction of the amine and the lactone ring of arctigenin produces corresponding ring-opened derivatives with a greater polarity than arctigenin, which can be used as a prodrug of arctigenin;

The ammonolysis derivatives generated by the reaction of arctigenin with propylamine and ethanolamine are new compounds, and the benzylamine ammonolysis derivatives of arctigenin are reported compounds. The present invention uses benzylamine as both a reaction raw material and a solvent to prepare burdock The benzylamine aminolysis derivative of aglycon saves solvent and reduces economic cost.

The preparation process of arctigenin monodemethyl derivatives: add arctigenin and anhydrous pyridine into a round-bottomed flask, add anhydrous aluminum chloride to the flask in stages, after the addition is complete, reflux, and stop the reaction. The reaction solution was concentrated under reduced pressure, the residue was dissolved in a mixed solution of ethyl acetate and ethanol, pumped up, the filtrate was concentrated under reduced pressure, and the target compound was obtained by silica gel column chromatography.

The preparation process of arctigenin full demethylation derivatives: add arctigenin, glacial acetic acid, demethylation reagent hydrobromic acid solution into a round bottom flask, heat to reflux, and complete the reaction. Pour the reaction solution into water, adjust the pH value with sodium bicarbonate, extract with an appropriate amount of ethyl acetate, add anhydrous sodium sulfate to dry, filter, concentrate the filtrate under reduced pressure, and separate by silica gel column chromatography to obtain the target compound.

Although arctigenin semi-demethylation and full demethylation derivatives are reported compounds, the present invention uses arctigenin as the reaction raw material for the first time, and adopts hydrobromic acid as the demethylation reagent to prepare the full demethylation of arctigenin Derivatives: using pyridine as both a base and a solvent to prepare semi-demethylated derivatives of arctigenin, eliminating solvents and reducing economic costs.

Preparation process of arctigenin aminomethylated derivatives: arctigenin, paraformaldehyde, disubstituted secondary amine and glacial acetic acid are added into a round-bottomed flask and heated for reaction. After the reaction stopped, the glacial acetic acid solvent was distilled off under reduced pressure, and then an appropriate amount of water was added to the reaction flask, and filtered. The filtrate was adjusted to pH with sodium carbonate aqueous solution, filtered, and the crude product was separated by preparative thin-layer chromatography or recrystallized to obtain the target compound.

The preparation process of arctigenin oxygen atom acylated derivatives: arctigenin reacts with acetic anhydride or benzoyl chloride or succinic anhydride under heating conditions, and the reaction process is monitored by thin-layer chromatography. After the reaction is completed, the reaction solution is post-treated, and purified by preparative thin-layer or silica gel column chromatography to obtain the corresponding acylate.

The preparation process of arctigenin alkali hydrolyzed derivatives: react arctigenin and diethylamine at room temperature, and stop the reaction. Concentrate under reduced pressure, add an appropriate amount of water to the residue, extract with ethyl acetate, combine the extracts, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain arctigenin hydrolyzed derivatives.

Uses of arctigenin derivatives:

The application of the present invention in the preparation of anticancer drugs, these compounds have the effect of inhibiting cell proliferation, and can be used as raw materials in the preparation of anticancer drugs alone or in combination with other drugs.

The present invention uses arctigenin as the lead compound to prepare derivatives and study its antitumor activity. The structural modification of arctigenin and the antitumor activity of its derivatives showed that the demethylated derivatives of arctigenin compound 4-5 had a stronger inhibitory effect on the growth of human gastric cancer SGC7901 than arctigenin; the ammonia of arctigenin The growth inhibitory effect of methylated compound 10 on human gastric cancer SGC7901 and human prostate cancer Du154 cells is stronger than that of arctigenin, and the growth inhibitory effect on human liver cancer HEPG-2 cells is similar to that of arctigenin; the sulfonate of arctigenin The growth inhibitory effect of compound 11 on human gastric cancer SGC7901 and human liver cancer HEPG-2 cells is stronger than that of arctigenin, and the growth inhibitory effect on human prostate cancer Du154 cells is similar to that of arctigenin; the acylated derivative of arctigenin The growth inhibitory effects of compounds 13-14 on human gastric cancer SGC7901, human liver cancer HEPG-2 and human prostate cancer Du154 cells were stronger than those of arctigenin. Therefore, compound 4-5 , compound 10-11 and compound 13-14 have very good development value in antitumor aspect, wherein compound 11 is a water-soluble compound, can be used as the injection of anticancer drug; The inhibition rate of gastric cancer SGC7901 is significantly stronger than that of arctigenin, and it has a good development prospect in anti-gastric cancer.

Preparation Example 1

Add 74.8 mg arctigenin and 2 mL ethanolamine solution into a round bottom flask, stir at room temperature, and stop the reaction. The reaction liquid was concentrated under reduced pressure, and the residual liquid was separated by high-efficiency preparative liquid phase to obtain ammonolysis derivative 1 of arctigenin , wherein compound 1 was a new compound.

Measuring conditions: INSTROM AV500

Solvent: _CDCl3

surface 1 compound 1 of ¹³ C-NMR and ¹ H-NMR NMR data

Preparation example 2

111.6mg of arctigenin was placed in a 25mL round bottom flask, 6.0mL of n-propylamine solution was added, stirred and dissolved at 25°C, and the reaction was stopped after 24 hours of reaction. The reaction liquid was concentrated under reduced pressure, and methanol was recrystallized to obtain compound 2 , wherein compound 2 was a new compound.

Measuring conditions: INSTROM AV500

Solvent: _CDCl3

surface 2 compound 2 of ¹³ C-NMR and ¹ H-NMR NMR data

Preparation example 3

Add 96mg arctigenin and 1mL benzylamine solution into a round bottom flask, and react at 160°C for 12 hours. Cool the reaction solution to room temperature, add 10% dilute hydrochloric acid to the reaction solution, extract with ethyl acetate 3-5 times, combine the extracts, concentrate, and then use high-efficiency preparative liquid phase for separation to obtain compound 3 .

Measuring conditions: INSTROM AV500

Solvent: _CDCl3

surface 3 compound 3 of ¹³ C-NMR and ¹ H-NMR NMR data

Preparation example 4

Add 372mg arctigenin and 3.0mL anhydrous pyridine into the reaction flask, gradually raise the temperature to 115°C, add 399mg anhydrous aluminum chloride into the flask three times, react for 3 hours, and end the reaction. The reaction solution was concentrated under reduced pressure, the residue was extracted three times with ethyl acetate: ethanol (2:1), the extracts were combined, concentrated under reduced pressure, and silica gel column chromatography with dichloromethane: methanol system gradient elution to obtain compound 4 .

Measuring conditions: INSTROM AV500

Solvent: MeOD

surface 4 compound 4 of ¹³ C-NMR and ¹ H-NMR NMR data

Preparation example 5

Add 100mg arctigenin and 2mL glacial acetic acid into the reaction flask, stir to dissolve, heat up to 70°C, add 0.2mL of demethylation reagent 48% hydrobromic acid aqueous solution, then raise the temperature to 110°C for 16 hours to end the reaction , cooled to room temperature. Pour the reaction solution into an equal volume of water, adjust the pH to 6-7 with saturated sodium bicarbonate, extract three times with ethyl acetate, combine the extracts, add anhydrous sodium sulfate to dry, filter, and concentrate the filtrate under reduced pressure. Silica gel column chromatography with dichloromethane:methanol (40:1) gradient elution to obtain compound 5 .

Measuring conditions: INSTROM AV500

Solvent: DMSO

Table 5 13C-NMR and 1H-NMR nuclear magnetic resonance data of compound 5 no C h 1 128.84 2 115.57 6.62 (1H, d, J = 1.95 Hz) 3 145.10 4 143.79 5 116.58 6.62 (1H, d, J =7.90 Hz) 6 120.13 6.34 (1H, dd, J =7.98, 1.95 Hz) 7 33.35 2.72 (2H, m) 8 45.64 2.59 (1H, dd, J =3.25, 3.25 Hz) 9 178.47 1' 129.56 2' 115.44 6.48 (1H, d, J = 1.95 Hz) 3' 145.10 4' 143.63 5' 115.95 6.65 (1H, d, J =7.95 Hz) 6' 119.19 6.43 (1H, dd, J =7.98, 1.95 Hz) 7' 36.65 2.32 (2H, m) 8' 40.80 2.45 (1H, dd, J =3.80, 3.95 Hz) 9' 70.58 3.97 (1H, t), 3.80 (1H, t)

Preparation example 6

Add arctigenin, paraformaldehyde and glacial acetic acid to the reaction flask, then add dimethylamine hydrochloride, diethylamine hydrochloride, piperidine, hydroxyethylpiperazine and anhydrous piperazine to the reaction flask respectively , heating the reaction, and monitoring the progress of the reaction by thin layer chromatography (TLC). After stopping the reaction, distill off the glacial acetic acid solvent under reduced pressure, then add an appropriate amount of aqueous solution, filter, adjust the pH value of the filtrate to 7-8 with 5% aqueous sodium carbonate solution, filter, and recrystallize the solid with methanol or prepare a thin layer for purification to obtain ammonium Compounds 6-10 , compounds 6-7 and 9-10 are all new compounds .

Measuring conditions: INSTROM AV500

Solvent: _CDCl3

surface 6 compound 6 of ¹³ C-NMR and ¹ H-NMR NMR data

Measuring conditions: INSTROM AV500

Solvent: _CDCl3

surface 7 compound 7 of ¹³ C-NMR and ¹ H-NMR NMR data

Measuring conditions: INSTROM AV500

Solvent: _CDCl3

surface 8 compound 8 of ¹³ C-NMR and ¹ H-NMR NMR data (CDCl ₃ )

Measuring conditions: INSTROM AV500

Solvent: _CDCl3

surface 9 compound 9 of ¹³ C-NMR and ¹ H-NMR NMR data (CDCl ₃ )

Measuring conditions: INSTROM AV500

Solvent: _CDCl3

surface 10 compound 10 of ¹³ C-NMR and ¹ H-NMR NMR data (CDCl ₃ )

Preparation example 7

Add 111.6mg arctigenin, 1.2mL acetic anhydride and 0.6mL glacial acetic acid into a round bottom flask, add dropwise 0.12mL mixed acid (glacial acetic acid: sulfuric acid = 1:1), and stir to dissolve. Stir at room temperature for 12 hours to stop the reaction. The reaction solution was adjusted to pH 6-7 with 5% NaCO ₃ , concentrated under reduced pressure, added three volumes of ethanol, ultrasonically extracted, filtered, and the filtrate was concentrated and recrystallized from ethanol to obtain the sulfonylated derivatives of arctigenin, compound 11 , compound 11 for new compounds.

Measuring conditions: INSTROM AV500

Solvent: _D2O

surface 11 compound 11 of ¹³ C-NMR and ¹ H-NMR NMR data

Preparation example 8

111.6mg arctigenin and 3mL benzoyl chloride were added into a round bottom flask and reacted at 40°C for 2 hours. After the reaction was completed, 2 mL of dichloromethane was added, washed twice with an equal volume of 10% aqueous sodium hydroxide solution, the organic layer was dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated and purified by preparative thin-layer chromatography to obtain compound 12 .

Measuring conditions: INSTROM AV500

Solvent: _CDCl3

surface 12 compound 12 of ¹³ C-NMR and ¹ H-NMR NMR data

Preparation example 9

Add 372mg arctigenin, 50mg sodium acetate, 3mL acetic anhydride and 3mL dichloromethane into the reaction flask, react at 38°C for 5 hours, stop the reaction, and cool to room temperature. Add an equal volume of 10% dilute hydrochloric acid, saturated sodium bicarbonate solution, saturated sodium chloride solution and water to the reaction solution, wash once each, dry over anhydrous sodium sulfate, filter, concentrate, and the residue is subjected to silica gel column chromatography with dichloromethane : Methanol (60:1) system for gradient elution to obtain compound 13 .

Measuring conditions: INSTROM AV500

Solvent: _CDCl3

surface 13 compound 13 of ¹³ C-NMR and ¹ H-NMR NMR data

Preparation example 10

372mg arctigenin, 3mL triethylamine and 15mL CH ₂ Cl ₂ were added to the reaction flask, and 1g succinic anhydride was added under the condition of stirring, and the reaction was stopped after 7 minutes at 40°C. The reaction solution was washed twice with an appropriate amount of 10% HCl aqueous solution, and then washed once with water, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and dried to obtain compound 14 .

Measuring conditions: INSTROM AV500

Solvent: _CDCl3

Table 14 13C-NMR nuclear magnetic resonance data of compound 14 No. _δC 1 138.55 2 111.52 3 151.11 4 136.75 5 122.54 6 120.57 7 34.62 8 46.37 9 178.59 1' 130.32 2' 111.99 3' 149.06 4' 147.89 5' 113.38 6' 121.40 7' 38.08 8' 40.99 9' 71.26 10 170.30 11 28.7 12 28.9 13 176.89 -OCH ₃ *3 55.89,55.86,55.84

Preparation example 11

Add 500mg arctigenin, 0.1mL diethylamine and 10mL methanol into the reaction flask, stir at room temperature for 24 hours, and stop the reaction. The reaction solution was concentrated under reduced pressure, an equal volume of water was added, extracted three times with ethyl acetate, the extracts were combined, the ethyl acetate extract was washed twice with water, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 15 .

Measuring conditions: INSTROM AV500

Solvent: Pyridine

Table 15 13C-NMR nuclear magnetic resonance data of compound 15 (Pyr) No. _δC 1 132.16 2 112.69 3 148.33 4 146.55 5 116.34 6 122.11 7 35.27 8 48.61 9 177.89 1' 134.39 2' 113.49 3' 149.68 4' 148.52 5' 114.04 6' 122.37 7' 35.37 8' 45.92 9' 62.18 -OCH ₃ *3 55.76, 55.73, 56.02

Experimental example 1

The compound of formula (I) and its anti-tumor activity of the present invention are studied, and the compound of formula (I) is compared with the growth inhibitory effect on different malignant tumor cells.

The tumor cells sensitive to arctigenin were selected to conduct MTT experiments on arctigenin and its derivatives. Human cancer strains were cultured in RPMI-1640 medium containing 10% calf serum at 37°C and 5% CO ₂ , and the medium was changed for 48 hours. After the cells grew to a single layer, they were digested and passaged with 0.25% trypsin. The cell suspension with a cell concentration of 2×10 ⁴ /mL was inoculated in a 96-well cell culture plate with a volume of 200 μL per well. After culturing at 37°C and 5% CO ₂ for 24 hours, different concentrations of therapeutic drugs were added. 3 duplicate wells; another control group 1 (using RPMI-1640 culture solution containing the same amount of DMSO and 10% calf serum) was set up. After culturing for 72 hours, aspirate the culture solution, add 200 μL of serum-free RPMI-1640 culture solution containing MTT (final concentration 0.5 mg/mL) to each well, continue to cultivate for 4 hours, discard the supernatant solution, add 100 μL DMSO, and Vibrate on a micro-shaker for 5 minutes to make it fully mixed, measure its absorbance (A value) with a microplate reader (Tecan Infinite M200), the absorption wavelength is 570 nm, and the cell proliferation inhibition rate=(1-treatment group A value/control Group A value) × 100﹪.

1. Arctigenin structural derivative compound 1 and arctigenin, using human colon cancer cell line HCT116, human gastric cancer cell line MGC803, human lung cancer cell line NCI-H460, human pancreatic cancer cell line PANC-1 and esophageal cancer cell line TE-1 was evaluated for its activity. All cell lines were purchased from the Institute of Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences. The following is the half inhibitory concentration (IC ₅₀ ) measured at 3 days of administration: unit (µmol/L)

Table 16 Antitumor activity results of arctigenin and compound 1 compound HCT116 MGC-803 NCI-H460 PANC-1 TE-1 Arctigenin 4.99 20 100 19.51 2.78 Compound 1 72.03 83.82 120.97 68.75 >100

The results showed that arctigenin had high inhibitory activity on HCT116, TE-1, PANC-1, and MGC-803, with IC ₅₀ of 4.99µmol/L, 2.78µmol/L, 19.51µmol/L, and 20µmol/L, respectively. The inhibitory effect of -H460 was poor, and the inhibition rate of 100 μmol/L arctigenin on NCI-H460 was 29.8%, which indicated that the anticancer activity of arctigenin was cell-selective. Arctigenin structural modifier Compound 1 has inhibitory effects on the proliferation of HCT116, NCI-H460, and PANC-1 cells, but has a weaker inhibitory effect on TE-1 ( see Table 16 ).

2. 14 arctigenin structural modifier compounds 2-15 and arctigenin were used in human liver cancer cell line Bel7402, human gastric cancer cell line SGC7901, human lung cancer cell line NCI-H460, human prostate cancer cell line Du145 and human liver cancer cell line Strain HEPG-2 was evaluated for its activity. All cell lines were purchased from the Institute of Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences.

surface 17 Comparison of growth inhibitory effects of arctigenin and its structural derivatives on different types of tumor cells

The results showed that: under the same concentration as arctigenin, the 14 structural modifiers of arctigenin could inhibit the growth of cells to varying degrees, and the growth inhibitory effects of each sample on different types of tumor cells were also different. It can be seen from the experimental results that the growth inhibitory effect of each sample on human liver cancer cell Bel7402 cells is weaker than that of arctigenin. Compared with Bel7402 cells, compound 4 , compound 5 , compound 8-11 and compound 13-14 had stronger growth inhibitory effects on human gastric cancer cell SGC7901 cells, and the inhibition rates were 57.03±2.14, 62.51±5.54, 55.26±1.89, 51.26 ±2.47, 56.26±2.68, 57.18±2.33, 68.50±1.16 and 70.13±2.05; compared with Bel7402 cells, the growth inhibitory effects of compounds 9-11 and 13-14 on human prostate cancer Du145 cells were similar to those of arctigenin , the inhibitory rates were 68.74±4.19, 74.95±5.63, 70.46±5.19, 72.35±3.17 and 75.61±2.88, the growth inhibitory effect of compound 4 and compound 5 on Du145 was slightly weaker than that of arctigenin, and the inhibitory rates were 50.86±6.42 and 61.62±2.22, but the growth inhibitory effect of other derivatives on Du145 was lower than that of arctigenin; compound 10-11 and compound 13-14 showed strong growth inhibitory effect on human liver cancer HEPG-2 cells, and the inhibition rate 52.37±1.72, 59.35±2.31, 63.23±2.74, and 69.74±2.92, respectively ; compounds 4-5 and compounds 8-9 showed growth inhibitory effects on human liver cancer HEPG-2 cells, which were similar to those of arctigenin, and the inhibition rates were 45.65±2. 5.32, 47.83±3.29, 47.19±2.13 and 50.78±1.84; other derivatives were weaker than arctigenin ( see Table 17 ).

The above percentages are volume percentages.

The advantages of the present invention are:

The present invention uses arctigenin, a traditional Chinese medicine, as a lead compound to carry out structural transformation and then develop new drugs. It is expected to improve the water solubility of arctigenin, improve bioavailability, and facilitate dosage forms, and to find new anti-tumor drugs that are safer, more effective, less toxic and more convenient to use. . The inhibitory effect of the invention on the growth of human gastric cancer cells, liver cancer cells and prostate cancer cells is obviously stronger than that of arctigenin itself.

Description of drawings

Figure 1 is the H NMR spectrum of arctigenin.

Figure 2 is the carbon nuclear magnetic resonance spectrum of arctigenin.

Fig. 3 is the hydrogen spectrum of compound 1 , the ammonolysis derivative of arctigenin.

Fig. 4 is the carbon spectrum of the ammonolysis derivative compound 1 of arctigenin.

Fig. 5 is the hydrogen spectrum of compound 2 , the ammonolysis derivative of arctigenin.

Fig. 6 is the carbon spectrum of the ammonolysis derivative compound 2 of arctigenin.

Fig. 7 is the hydrogen spectrum of compound 3 , the ammonolysis derivative of arctigenin.

Fig. 8 is the carbon spectrum of compound 3 , the ammonolysis derivative of arctigenin.

Fig. 9 is the hydrogen spectrum of compound 4 , a monodemethylated derivative of arctigenin.

Fig. 10 is the carbon spectrum of compound 4 , a monodemethylated derivative of arctigenin.

Figure 11 is the hydrogen spectrum of compound 5 , a perdemethylated derivative of arctigenin.

Fig. 12 is the carbon spectrum of compound 5 , a perdemethylated derivative of arctigenin.

Fig. 13 is the hydrogen spectrum of compound 6 , an aminomethylated derivative of arctigenin.

Fig. 14 is the carbon spectrum of compound 6 , an aminomethylated derivative of arctigenin.

Fig. 15 is the hydrogen spectrum of compound 7 , an aminomethylated derivative of arctigenin.

Fig. 16 is the carbon spectrum of compound 7 , an aminomethylated derivative of arctigenin.

Fig. 17 is the hydrogen spectrum of compound 8 , an aminomethylated derivative of arctigenin.

Fig. 18 is a carbon spectrum of compound 8 , an aminomethylated derivative of arctigenin.

Fig. 19 is the hydrogen spectrum of compound 9 , an aminomethylated derivative of arctigenin.

Fig. 20 is the carbon spectrum of compound 9 , an aminomethylated derivative of arctigenin.

Fig. 21 is the hydrogen spectrum of compound 10 , an aminomethylated derivative of arctigenin.

Fig. 22 is a carbon spectrum of compound 10 , an aminomethylated derivative of arctigenin.

Fig. 23 is the hydrogen spectrum of Compound 11 , a sulfonylated derivative of arctigenin.

Fig. 24 is a carbon spectrum of compound 11 , a sulfonylated derivative of arctigenin.

Fig. 25 is the hydrogen spectrum of Compound 12 , an acylated derivative of arctigenin.

Fig. 26 is a carbon spectrum of compound 12 , an acylated derivative of arctigenin.

Fig. 27 is the hydrogen spectrum of compound 13 , an acylated derivative of arctigenin.

Fig. 28 is a carbon spectrum of compound 13 , an acylated derivative of arctigenin.

Fig. 29 is a carbon spectrum of compound 14 , an acylated derivative of arctigenin.

Fig. 30 is a carbon spectrum of compound 15 , a hydrolyzed derivative of arctigenin.

Claims (10)

1. arctigenin derivatives, characterized in that: take arctigenin as a lead compound to carry out structural modification, and its general structural formula is (І); (І). 2. The arctigenin derivative according to claim 1, whose structural characteristics are R=NHR'', R'=OH, R ₁ =CH ₃ , R ₂ =R ₃ =R ₄ =R ₅ =H, R ₆ =R ₇ =CH ₃ , using chemical methods, the lactone ring of arctigenin can be opened by ammonolysis to obtain ammonolysis derivatives; The structure of the ammonolytic derivatives of arctigenin is R=NHR'', R''=CH ₂ CH ₂ CH ₃ , CH ₂ CH ₂ OH and CH ₂ C ₆ H ₅ , the substituted propylamine, ethanolamine and benzylamine Ammonolysis reaction of ester with the lactone ring of arctigenin generates corresponding ring-opened derivatives with greater polarity than arctigenin, which can be used as prodrugs of arctigenin. 3. The arctigenin derivative according to claim 1, whose structural characteristics are R, R'=O, R ₁ =R ₂ =R ₃ =R ₄ =R ₅ =H, R ₆ =CH ₃ or H, R ₇ =CH ₃ or H, where arctigenin is converted into semi-demethylated or fully demethylated derivatives by chemical methods. 4. The arctigenin derivative according to claim 1, which has the structural characteristics of R, R'=O, R ₁ =CH ₃ , R ₂ =H, R ₃ =CH ₂ NR ₁ 'R ₂ ', R ₄ =R ₅ =H, R ₆ =R ₇ =CH ₃ , which are converted into nitrogen-containing derivatives of arctigenin by chemical methods through aminomethylation reaction. 5. The arctigenin derivative according to claim 4, wherein the structure is characterized by R ₁ '=CH ₃ , CH ₂ CH ₃ , R ₂ '=CH ₃ , CH ₂ CH; or , except for the nitrogen-containing derivatives of the piperidine ring, the other compounds are all new compounds. 6. The arctigenin derivative according to claim 1, whose structural characteristics are R, R'=O, R ₁ =CH ₃ , R ₂ =R ₃ =H, R ₄ =R ₅ =SO ₃ Na, R ₆ = R ₇ =CH ₃ , which is converted into a sulfonate derivative of arctigenin by chemical means through sulfonylation on the aromatic ring. 7. The arctigenin derivative according to claim 1, whose structure is characterized by R, R'=O, R ₁ =CH ₃ , R ₂ =COCH ₃ , COC ₆ H ₅ or COCH ₂ CH ₂ COOH, R ₃ =R ₄ =R ₅ =H, R ₆ =R ₇ =CH ₃ , where R ₂ is the side chain part of the arctigenin molecular formula hydroxyl, which is converted into a fat-soluble derivative or Water-soluble derivatives. 8. according to the described arctigenin derivative of claim 7, it is characterized in that: the oxygen atom acylation derivative of arctigenin adopts dichloromethane as solvent, adds appropriate amount of triethylamine and sodium acetate, heats and refluxes for 7 minutes to Such derivatives were prepared in 5 hours. 9. The arctigenin derivative according to claim 1, the structure of the hydrolyzed derivative of arctigenin is R=R'=OH, R ₁ =CH ₃ , R ₂ =R ₃ =R ₄ =R ₅ = H, R ₆ =R ₇ =CH ₃ , hydrolyzing arctigenin under alkaline conditions to obtain an alkali hydrolysis derivative of arctigenin lactone ring opening. 10. The arctigenin derivatives according to claim 1, the application in the preparation of anticancer drugs, is characterized in that: these compounds have the effect of inhibiting cell proliferation, and can be used alone or in combination with other drugs as raw materials for anticancer drugs in the preparation.