CN115197236B - Linear type glabra A analogue and preparation and application thereof - Google Patents

Abstract

The invention discloses a linear Glycyrrhiza A analogue, which has the following structural formula I: The invention also provides a method for preparing linear Glycyrrhiza A analogues. Methanol is used as the solvent, and compound 23a-23j is used as the raw material. After the temperature is raised and dissolved, the reaction is stirred at 0°C-5°C and divided into 2 parts within 1-3 hours. - Add NaBH ₄ dropwise for 5 times, and add 5% HCl solution dropwise to the reaction solution to terminate the reaction. After drying part of the methanol, extract with ethyl acetate, combine the organic layers, and wash with saturated NaHCO ₃ solution and saturated brine in sequence. Dry over sodium sulfate, filter, and recrystallize from methanol to obtain linear Glycyrrhiza A analogue. In vitro anti-tumor experiments show that the linear Licorice A analogue provided by the invention has a strong inhibitory effect on leukocytes, lung cancer cells, cervical cancer cells and human breast cancer cells.

Description

Linear Licorice A analogues and their preparation and use

Technical field

The invention belongs to the field of medicinal chemistry. More specifically, the present invention relates to a Glycyrrhiza A analogue, 3-aryl-6,7-pyranocoumarin, and its preparation and use.

Background technique

Cancer is a malignant tumor that originates from epithelial tissue. Cancer cells can appear almost anywhere in the body. These cells grow uncontrollably, spread and attack surrounding normal tissues, and may metastasize to form tumors in multiple parts of the body. According to the World Health Organization, in 2022, nearly 19.3 million people will be diagnosed with new cancers worldwide, and nearly 10 million will die from cancer. Its fatality rate is much higher than AIDS and tuberculosis combined. At present, the main medical treatment for cancer is surgical resection. In order to better treat cancer, the U.S. Food and Drug Administration has approved the marketing of anti-cancer drugs such as paclitaxel and vincristine. However, due to the poor targeting selectivity of drug molecules and The bioavailability is low. While attacking cancer cells, it can also cause damage to normal cells, causing patients to suffer side effects such as hair loss, low immunity, and weight loss. Therefore, the search for highly efficient and low-toxic anticancer drugs has become one of the hot topics in today's scientific research community.

Coumarin is a compound with a benzopyrone structure. The benzene ring and α-pyrone ring are the core components of coumarin. Due to its conformational relationship, its chemical properties are stable and can be used in a variety of ways. The introduction of functional groups leads to more coumarin analogs. Coumarins can be divided into simple coumarins, furanocoumarins, pyanocoumarins and other coumarins according to their basic structure. Among them, pyanocoumarin derivatives are an important component of natural active products, including anti-cancer, antioxidant, anti-inflammatory, anti-HIV, etc. in recent years. Many anti-cancer active ingredients have been extracted from coumarin, providing directions for the development of new anti-cancer drugs.

Dalbergia benthamii Prain is a woody vine whose medicinal parts are stems. It is mainly distributed in Guangdong, Guangxi, Hainan and other places. A linear pyranocoumarin, Licorice A, was isolated and identified from the strong medicine Dalbergia benthamii Prain. Pharmacological experiments have proven that it has obvious scavenging effects on both DPpH free radicals and ABTS+˙ free radicals. , has a certain inhibitory effect on tumor cells. However, this compound has poor water solubility and a certain degree of toxicity. If its structure can be optimized to improve water solubility and reduce toxicity, the possibility of using Licorice A derivatives as clinical drugs will be improved.

Contents of the invention

It is an object of the present invention to solve at least the above-mentioned problems and to provide at least the advantages to be explained later.

The present invention uses fully synthesized intermediate coumarin 9 and phenylacetic acid derivatives as raw materials to synthesize a series of linear Glycyrrhiza A analogues 3-aryl-6,7-pyranocoumar with novel structures, high efficiency and low toxicity. Elements 24a-24j.

In order to achieve these objects and other advantages of the present invention, a linear Glycyrrhiza A analogue is provided, which has the following structural formula I:

General formula I includes compounds 24a-24j;

in,

A method for preparing the linear Glycyrrhiza A analogue, using methanol as the solvent and compounds 23a-23j as raw materials, after heating up and dissolving, place it at 0℃-5℃ for stirring reaction, and divide into 2-2 times within 1-3h NaBH ₄ was added dropwise 5 times, and 5% HCl solution was added dropwise to the reaction solution to terminate the reaction. After part of the methanol was rotated dry, extracted with ethyl acetate, the organic layers were combined, washed with saturated NaHCO ₃ solution, saturated brine, and anhydrous. Dry with sodium sulfate, filter, and recrystallize from methanol to obtain linear Glycyrrhiza A analogue 3-aryl-6,7-pyranocoumarin 24a-24j;

Among them, compounds 23a-23j have the following structural formula II:

Preferably, under the protection of an inert gas, the intermediate coumarin 9 and the phenylacetic acid derivative are used as raw materials, in an acetic anhydride/triethylamine reaction system, with weak base triethylamine as the catalyst and acetic anhydride as the solvent. The reaction was heated under reflux. After the reaction, water was added, and the mixture was extracted with ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate overnight, and purified by column chromatography to obtain compounds 23a-23j.

Preferably, 2,4,6-trihydroxyacetophenone and 3,3-dimethacrylic acid are used as raw materials, and anhydrous dioxane is used as a solvent oil bath to heat and reflux the reaction. After the reaction is completed, ice is poured into Adjust the pH to neutral with water and saturated potassium carbonate, filter, and separate the crude product by silica gel column chromatography to obtain the intermediate coumarin 9.

A use of the linear Glycyrrhiza A analogue, the linear Glycyrrhiza A analogue 3-aryl-6,7-pyranocoumarin is used for preparing anti-tumor drugs.

Preferably, the linear Glycyrrhiza A analogue 3-aryl-6,7-pyranocoumarin is combined with excipients to prepare injections, tablets, pills, capsules, suspensions or emulsions.

Preferably, the auxiliary materials are ethanol, propylene glycol, polyethylene glycol, diethylene glycol, triacetin, glycerin, dextrin, povidone, stearyl alcohol, stearic acid, microcrystalline cellulose, starch, One or more of lactose, mannitol, sodium bicarbonate, calcium carbonate, low-substituted hydroxypropyl methylcellulose, magnesium stearate, and talc.

The present invention at least includes the following beneficial effects: the linear Glycyrrhiza A analogue 3-aryl-6,7-pyranocoumarin provided by the present invention shows that the compound has strong anti-tumor activity through in vitro anti-tumor experiments. Used in the preparation of anti-tumor drugs, it can be made into common pharmaceutical dosage forms, including injections, tablets, pills, capsules, suspensions or emulsions.

Other advantages, objects, and features of the present invention will be apparent in part from the description below, and in part will be understood by those skilled in the art through study and practice of the present invention.

Detailed ways

The present invention will be described in further detail below so that those skilled in the art can implement it according to the text of the description.

It should be understood that terms such as "having," "comprising," and "including" as used herein do not exclude the presence or addition of one or more other elements or combinations thereof.

It should be noted that the experimental methods described in the following embodiments, unless otherwise specified, are all conventional methods, and the reagents and materials, unless otherwise specified, can be obtained from commercial sources.

Synthetic route of linear Glycyrrhiza A analogue 3-aryl-6,7-pyranocoumarin:

The invention provides a method for preparing the linear Glycyrrhiza A analogue. Methanol is used as a solvent, and compounds 23a-23j (1-10mmol) are used as raw materials. After being heated and dissolved, they are stirred at 0°C-5°C. Reaction, add NaBH ₄ (5-50mmol) dropwise in 2-5 times within 1-3h, dropwise add acid solution such as HCl or sulfuric acid into the reaction solution to complete the reaction, spin dry part of the methanol, extract with ethyl acetate, and combine the organic acids layer, washed with saturated NaHCO ₃ solution, saturated brine, dried over anhydrous sodium sulfate, filtered, and recrystallized from methanol to obtain the linear Glycyrrhiza A analogue 3-aryl-6,7-pyranocoumarin 24a- 24j.

In a technical solution, under the protection of inert gas, the intermediate coumarin 9 (1-10mmol) and the phenylacetic acid derivative (1-10mmol) are used as raw materials, in an acetic anhydride/triethylamine reaction system, with Weak base triethylamine (0.1-5mmol) is used as the catalyst and acetic anhydride (10-100mmol) is used as the solvent. The reaction is heated under reflux. After the reaction is completed, add water, extract with ethyl acetate, combine the organic layers, and dry over anhydrous sodium sulfate overnight. Purification by column chromatography gave compounds 23a-23j.

In one technical solution, 2,4,6-trihydroxyacetophenone (1-50mmol) and 3,3-dimethacrylic acid (1-50mmol) are used as raw materials, and anhydrous dioxane is used as the solvent. Heat the oil bath for reflux reaction. After the reaction is completed, pour ice water, adjust the pH to neutral with saturated potassium carbonate, filter, and separate the crude product by silica gel column chromatography to obtain the intermediate coumarin 9.

<Example 1>

A preparation method for linear Glycyrrhiza A analogue 3-aryl-6,7-pyranocoumarin 24a, including the following steps:

Step 1. 2,4,6-trihydroxyacetophenone (10mmol) and 3,3-dimethacrylic acid (22mmol) are used as raw materials, and anhydrous dioxane is used as the solvent oil bath for heating and reflux reaction. After the reaction is completed , pour ice water, adjust the pH to neutral with saturated potassium carbonate, filter, and separate the crude product by silica gel column chromatography to obtain the white transparent crystal intermediate coumarin 9.

Step 2: Under _N2 gas protection, use intermediate coumarin 9 (1mmol) and p-methylphenylacetic acid (1mmol) as raw materials, in an acetic anhydride/triethylamine reaction system, use weak base triethylamine (1.5 mmol) as the catalyst and acetic anhydride (40 mmol) as the solvent. The reaction was heated under reflux. After the reaction, water was added, extracted with ethyl acetate, the organic layers were combined, dried over anhydrous sodium sulfate overnight, and purified by column chromatography to obtain compound 23a.

Compound 23a, namely 4,2”,2”-trimethyl-3-p-methoxyphenyl-5-acetoxy-2”H,3”H-6,7-pyranocoumarin-4 "-Ketone: white single crystal, yield 30%, mp177.2-179.5℃; HR-MS (ESI) m/z: calculated for C ₂₄ H ₂₂ O ₇ [M+H] ⁺ :423.1431, found: 423.1434. ¹ H NMR (400MHz, CDCl ₃ ) δ7.18 (d, J = 8.4Hz, 2H), 6.99 (d, J = 6.9Hz, 2H), 6.82 (s, 1H), 3.86 (s, 3H, 4′ -OCH ₃ ),2.72(s,2H),2.45(s,3H,4-CH ₃ ),2.37(s,3H,12-CH ₃ ),1.50(s,6H,2″-2×CH ₃ ) . ¹³ C NMR (126MHz, CDCl ₃ ) δ 189.73, 169.32, 161.80, 159.75, 159.51, 157.85, 149.10, 146.92, 131.34, 126.77, 126.17, 114.04, 110.46, 109.59, 103. 69,80.15,55.33,49.80,27.23,21.67, 20.45.

Step 3. Use methanol as the solvent and compound 23a (8mmol) as the raw material. After heating up and dissolving, place it at 0℃-5℃ for stirring reaction. Add NaBH ₄ (40mmol) dropwise in three times within 1.5h. Add 9-10 drops of 5. % HCl in the reaction solution to complete the reaction, spin dry part of the methanol, extract with ethyl acetate, combine the organic layers, wash with saturated NaHCO ₃ solution, saturated brine, dry with anhydrous sodium sulfate, filter, and recrystallize with methanol to obtain a straight line Licorice A analogue 3-aryl-6,7-pyranocoumarin.

Linear Glycyrrhiza A analogue 3-aryl-6,7-pyranocoumarin 24a, i.e. 4,2”,2”-trimethyl-3-(p-methoxyphenyl)-5-hydroxy --2”H,3”H-6,7-pyranocoumarin: orange crystal, yield 70%, mp261.4-263.2℃; HR-MS(ESI)m/z:calculated for C ₂₂ H ₂₂ O ₅ [M+H] ⁺ :367.1540, found: 367.1546. ¹ H NMR (500MHz, CDCl ₃ ) δ7.19 (d, J = 7.8 Hz, 2H), 6.96 (d, J = 7.8 Hz, 2H) ,6.45(s,1H),5.26(s,1H,5-OH),3.84(s,3H,4′-OCH ₃ ),2.59(s,2H),2.47(s,3H,4-CH ₃ ) ,1.93(s,2H),1.37(s,6H,2″-2×CH ₃ ). ¹³ C NMR (126MHz, CDCl ₃ )δ161.64,159.03,156.68,153.53,152.58,149.52,131.59,127.49,123.05, 113.89,103.67,103.26,97.96,74.91,55.29,31.78,26.45,21.38,16.65.

<Example 2>

A preparation method of linear Glycyrrhiza A analogue 3-aryl-6,7-pyranocoumarin 24b, including the following steps:

Step 1. 2,4,6-trihydroxyacetophenone (10mmol) and 3,3-dimethacrylic acid (22mmol) are used as raw materials, and anhydrous dioxane is used as the solvent oil bath for heating and reflux reaction. After the reaction is completed , pour ice water, adjust the pH to neutral with saturated potassium carbonate, filter, and separate the crude product by silica gel column chromatography to obtain the white transparent crystal intermediate coumarin 9.

Step 2: Under _N2 gas protection, use intermediate coumarin 9 (1mmol) and p-toluene acetic acid (1mmol) as raw materials, in an acetic anhydride/triethylamine reaction system, use weak base triethylamine (1.5mmol) The reaction was heated under reflux with acetic anhydride (40 mmol) as the catalyst. After the reaction, water was added, extracted with ethyl acetate, the organic layers were combined, dried over anhydrous sodium sulfate overnight, and purified by column chromatography to obtain compound 23b.

Compound 23b, namely 4,2”,2”-trimethyl-3-p-methylphenyl-5-acetoxy-2”H,3”H-6,7-pyranocoumarin-4” -Ketone: white solid, yield 31%, mp200.2-201.9℃; HR-MS (ESI) m/z: calculated forC ₂₄ H ₂₂ O ₆ [M+H] ⁺ :407.1484, found: 407.1486. ¹ H NMR (400MHz, CDCl ₃ ) δ7.28(d,J＝7.8Hz,2H),7.17(d,J＝8.0Hz,2H),6.67(s,1H),2.73(s,2H),2.48(s ,3H,12-CH ₃ ),2.42(s,6H,4-CH ₃ ),1.55(s,6H,2″-2×CH ₃ ). ¹³ C NMR (126MHz, CDCl ₃ )δ189.28,169.26,160.35 , 159.81,158.08,152.04,148.71,138.16,131.30,129.87,129.34,126.89,110.07, 109.73, 105.28,81.33,48.849.10, 21.37,21.13..

Step 3: Use methanol as the solvent and compound 23b (8mmol) as the raw material. After heating up and dissolving, stir the reaction at 0℃-5℃. Add NaBH ₄ (40mmol) dropwise in three times within 1.5h, and add 9-10 drops. 5% HCl was added to the reaction solution to complete the reaction. After part of the methanol was spun off, the mixture was extracted with ethyl acetate. The organic layers were combined, washed with saturated NaHCO ₃ solution and saturated brine, dried over anhydrous sodium sulfate, filtered, and recrystallized from methanol to obtain Linear Glycyrrhiza A analogue 3-aryl-6,7-pyranocoumarin 24b;

Linear Glycyrrhiza A analogue 3-aryl-6,7-pyranocoumarin 24b, i.e. 4,2”,2”-trimethyl-3-(p-methylphenyl)-5-hydroxy- -2”H,3”H-6,7-pyranocoumarin: white solid, yield 69%, mp260.0-261.5℃; HR-MS (ESI) m/z: calculated for C22H22O4[M+ H]+: 351.1588, found: 351.1589. ¹ H NMR (500MHz, CDCl3) δ7.22 (d, J = 7.3Hz, 2H), 7.14 (d, J = 7.4Hz, 2H), 6.44 (s, 1H) ,5.44(s,1H,5-OH),2.58(t,J＝6.0Hz,2H),2.45(s,3H,4′-CH3),2.37(s,3H,4-CH3),1.91(t ,J＝6.1Hz,2H),1.37(s,6H,2″-2×CH3) ¹³ C NMR(126MHz,CDCl3)δ161.61,156.73,153.55,152.72,149.67,137.43,132.33,130.21,129.16,123.31, 103.67,103.41,97.90,74.92,31.79,26.46,21.36,21.34,16.66.

<Example 3>

A preparation method of linear Glycyrrhiza A analogue 3-aryl-6,7-pyranocoumarin 24c, including the following steps:

Step 1. 2,4,6-trihydroxyacetophenone (10mmol) and 3,3-dimethacrylic acid (22mmol) are used as raw materials, and anhydrous dioxane is used as the solvent oil bath for heating and reflux reaction. After the reaction is completed , pour ice water, adjust the pH to neutral with saturated potassium carbonate, filter, and separate the crude product by silica gel column chromatography to obtain the white transparent crystal intermediate coumarin 9.

Step 2: Under _N2 gas protection, use intermediate coumarin 9 (1mmol) and p-fluorophenylacetic acid (1mmol) as raw materials, in an acetic anhydride/triethylamine reaction system, use weak base triethylamine (1.5mmol) ) as the catalyst, and acetic anhydride (40 mmol) as the solvent was heated to reflux. After the reaction, water was added, extracted with ethyl acetate, the organic layers were combined, dried over anhydrous sodium sulfate overnight, and purified by column chromatography to obtain compound 23c;

Compound 23c, namely 4,2”,2”-trimethyl-3-p-fluorophenyl-5-acetoxy-2”H,3”H-6,7-pyranocoumarin-4”- Ketone: white needle crystals, yield 35%, mp218.1-219.5℃; HR-MS (ESI) m/z: calculated forC ₂₃ H ₁₉ FO ₆ [M+H] ⁺ :411.1231, found:411.1234. ¹ H NMR (500MHz, CDCl ₃ ) δ7.24(d,J＝14.8Hz,2H),7.15(d,J＝7.8Hz,2H),6.82(s,1H),2.75(s,2H),2.44(s ,3H,4-CH ₃ ),2.33(s,3H,12-CH ₃ ),1.49(s,6H,2″-2×CH ₃ ). ¹³ C NMR (126MHz, CDCl ₃ )δ189.67,169.27,163.60 ,162.02,159.46,157.86,149.27,147.5 5,131.97,131.90,126.06,115.82,110.55,109.33,103.77,80.25,49.78,27.21,21.66,20.43.

Step 3: Use methanol as the solvent and compound 23c (8mmol) as the raw material. After heating up and dissolving, place it at 0℃-5℃ for stirring reaction. Add NaBH ₄ (40mmol) dropwise in three times within 1.5h, and add 9-10 times dropwise. Drop 5% HCl into the reaction solution to end the reaction, spin dry part of the methanol, extract with ethyl acetate, combine the organic layers, wash with saturated NaHCO3 solution, saturated brine, dry with anhydrous sodium sulfate, filter, and recrystallize with methanol to obtain Linear Glycyrrhiza A analogue 3-aryl-6,7-pyranocoumarin 24c.

Linear Glycyrrhiza A analogue 3-aryl-6,7-pyranocoumarin 24c, i.e. 4,2”,2”-trimethyl-3-(p-fluorophenyl)-5-hydroxy-- 2”H,3”H-6,7-pyranocoumarin: white solid, yield 72%, mp289.5-290.1℃; HR-MS (ESI) m/z: calculated for C ₂₁ H ₂₀ FO ₅ [M+Na] ⁺ :377.1152. ¹ H NMR (500MHz, CDCl ₃ ) δ7.24 (s, 2H), 7.12 (t, J = 7.8Hz, 2H), 6.46 (s, 1H), 5.29 (s ,1H,5-OH),2.59(t,J＝6.0Hz,2H),2.45(s,3H,4-CH ₃ ),1.94(t,J＝6.0Hz,2H),1.38(s,6H, 2″-2×CH ₃ ). ¹³ C NMR (126MHz, DMSO) δ162.87,160.92,157.19,155.24,153.26,150.93,133.04,132.97,121.36,115.38,106.60,104.35,96.42,75.43 ,31.78,26.64,21.90 ,17.67.

<Example 4>

A preparation method of linear Glycyrrhiza A analogue 3-aryl-6,7-pyranocoumarin 24d, including the following steps:

Step 1. 2,4,6-trihydroxyacetophenone (10mmol) and 3,3-dimethacrylic acid (22mmol) are used as raw materials, and anhydrous dioxane is used as the solvent oil bath for heating and reflux reaction. After the reaction is completed , pour ice water, adjust the pH to neutral with saturated potassium carbonate, filter, and separate the crude product by silica gel column chromatography to obtain the white transparent crystal intermediate coumarin 9.

Step 2: Under _N2 gas protection, use the intermediate coumarin 9 (1mmol) and p-chlorophenylacetic acid (22mmol) as raw materials, in an acetic anhydride/triethylamine reaction system, and use weak base triethylamine as the catalyst, The reaction was heated under reflux with acetic anhydride (40 mmol) as the solvent. After the reaction, water was added, extracted with ethyl acetate, the organic layers were combined, dried over anhydrous sodium sulfate overnight, and purified by column chromatography to obtain compound 23d.

Compound 23d, namely 4,2″,2″-trimethyl-3-p-chlorophenyl-5-acetoxy-2″H,3″H-6,7-pyranocoumarin-4″- Ketone: white needle crystals, yield 34%, mp230.1-231.2℃; HR-MS (ESI) m/z: calculated forC ₂₃ H ₁₉ ClO ₆ [M+H] ⁺ :427.0939, found: 427.0941. ¹ H NMR (400MHz, CDCl ₃ ) δ7.44(d,J＝8.5Hz,2H,),7.20(d,J＝8.3Hz,2H),6.83(s,1H),2.73(s,2H),2.45( s,3H,4-CH ₃ ),2.35(s,3H,12-CH ₃ ),1.51(s,6H,2″-2×CH ₃ ). ¹³ C NMR (126MHz, CDCl ₃ )δ189.15,169.21, 160.43,159.46,158.08,152.36,149.37,134.40,132.74,131.54,128.92,125.68,110.18,105.33,81.50, 22.15,21.1.13.

Step 3: Use methanol as the solvent and compound 23d (8mmol) as the raw material. After heating up and dissolving, place it at 0℃-5℃ for stirring reaction. Add NaBH ₄ (40mmol) dropwise in three times within 1.5h, and add 9-10 drops. Drop 5% HCl into the reaction solution to end the reaction, spin off part of the methanol, extract with ethyl acetate, combine the organic layers, wash with saturated NaHCO ₃ solution, saturated brine, dry over anhydrous sodium sulfate, filter, and recrystallize from methanol. The linear Glycyrrhiza A analogue 3-aryl-6,7-pyranocoumarin 24d was obtained.

Linear Glycyrrhiza A analogue 3-aryl-6,7-pyranocoumarin 24d, i.e. 4,2”,2”-trimethyl-3-(p-chlorophenyl)-5-hydroxy-- 2”H,3”H-6,7-pyranocoumarin: white solid, yield 69%, mp255.4-256.8℃; HR-MS (ESI) m/z: calculated for C ₂₁ H ₁₉ ClO ₄ [M+H] ⁺ :371.1042, found: 371.1043. ¹ H NMR (500MHz, CDCl ₃ ) δ7.40 (d, J = 7.5Hz, 2H), 7.21 (d, J = 7.5Hz, 2H), 6.73 (s,1H,H-8),2.70(t,J＝6.5Hz,2H),2.43(s,3H,4-CH ₃ ),1.82(t,J＝6.3Hz,2H),1.38(s, 6H,2″-2×CH ₃ ). ¹³ C NMR (126MHz, CDCl ₃ ) δ161.99,157.54,153.77,152.10,147.34,133.93,133.65,131.97,128.68,121.26,105.36,104.87,94.94, 75.90,31.34, 26.76,22.10,16.91.

<Example 5>

A preparation method of linear Glycyrrhiza A analogue 3-aryl-6,7-pyranocoumarin 24e, including the following steps:

Step 1. 2,4,6-trihydroxyacetophenone (10mmol) and 3,3-dimethacrylic acid (22mmol) are used as raw materials, and anhydrous dioxane is used as the solvent oil bath for heating and reflux reaction. After the reaction is completed , pour ice water, adjust the pH to neutral with saturated potassium carbonate, filter, and separate the crude product by silica gel column chromatography to obtain the white transparent crystal intermediate coumarin 9.

Step 2: Under _N2 gas protection, use intermediate coumarin 9 (1mmol) and 3,4-methylenedioxyphenylacetic acid (1mmol) as raw materials, in an acetic anhydride/triethylamine reaction system, use weak Alkali triethylamine (1.5mmol) was used as the catalyst and acetic anhydride (40mmol) was used as the solvent. The reaction was heated under reflux. After the reaction, water was added, extracted with ethyl acetate, the organic layers were combined, dried over anhydrous sodium sulfate overnight, and purified by column chromatography. , to obtain compound 23e.

Compound 23e, i.e. 4,2”,2”-trimethyl-3-(3’,4’-methylenedioxyphenyl)-5-acetoxy-2”H,3”H-6,7- Pyranocoumarin-4"-one: yellow solid, yield 38%, mp233.5-234.2℃; HR-MS (ESI) m/z: calculated of C ₂₄ H ₂₀ O ₈ [M+H] ⁺ :437.1226, found: 437.1228. ¹ H NMR (400MHz, CDCl ₃ ) δ6.89 (d, J＝7.9Hz, 1H, H-6′), 6.82 (s, 1H, H-8), 6.73-6.68 ( m,2H,H-2′,5′),6.02(s,2H,H-7′),2.73(s,2H,H-3″),2.45(s,3H,4-CH ₃ ),2.37 (s,3H,12-CH ₃ ),1.50(s,6H,2″-2×CH ₃ ). ¹³ C NMR (126MHz, CDCl ₃ )δ189.68,169.28,161.90,159.59,157.84,149.18,147.83,147.42 ,127.54,126.66,123.70,110.44,109.44,108.57,103.71,101.33,80.19,49.79,25.66,21.66,20.43.

Step 3. Use methanol as the solvent and compound 23e (8mmol) as the raw material. After heating up and dissolving, place it at 0℃-5℃ for stirring reaction. Add NaBH ₄ (40mmol) dropwise in three times within 1.5h, and add 9-10 times dropwise. Drop 5% HCl into the reaction solution to end the reaction, spin off part of the methanol, extract with ethyl acetate, combine the organic layers, wash with saturated NaHCO ₃ solution, saturated brine, dry over anhydrous sodium sulfate, filter, and recrystallize from methanol. The linear Glycyrrhiza A analogue 3-aryl-6,7-pyranocoumarin 24e was obtained.

Linear Glycyrrhiza A analogue 3-aryl-6,7-pyranocoumarin 24e, i.e. 4,2”,2”-trimethyl-3-(3’,4’-methylenedioxyphenyl )-5-Hydroxy--2”H,3”H-6,7-pyranocoumarin: white solid, yield 71%, mp253.1-253.8℃; HR-MS (ESI) m/z: calculated for C ₂₂ H ₂₀ O ₆ [M+H] ⁺ :381.1327. ¹ H NMR(500MHz, CDCl ₃ )δ6.77(d,J＝7.6Hz,1H),6.66-6.61(m,2H),6.35 (s,1H),5.89(s,2H),5.55(s,1H,5-OH),2.51(t,J＝6.1Hz,2H),2.39(s,3H,4-CH ₃ ),1.83( t, J＝6.2Hz, 2H), 1.29 (s, 6H, 2″-2×CH ₃ ). ¹³ CNMR (126MHz, CDCl ₃ ) δ160.64,155.81,152.41,151.80,149.37,146.57,146.05,127.83,122.80 ,121.69,109.76,107.37,102.54,100.08,96.78,73.92,30.71,25.40,20.35,15.60.

<Example 6>

A preparation method of linear Glycyrrhiza A analogue 3-aryl-6,7-pyranocoumarin 24f, including the following steps:

Step 1. 2,4,6-trihydroxyacetophenone (10mmol) and 3,3-dimethacrylic acid (22mmol) are used as raw materials, and anhydrous dioxane is used as the solvent oil bath for heating and reflux reaction. After the reaction is completed , pour ice water, adjust the pH to neutral with saturated potassium carbonate, filter, and separate the crude product by silica gel column chromatography to obtain the white transparent crystal intermediate coumarin 9.

Step 2: Under _N2 gas protection, use intermediate coumarin 9 (1mmol) and 2-chloro-4-fluorophenylacetic acid (1mmol) as raw materials, in an acetic anhydride/triethylamine reaction system, use a weak base Triethylamine (1.5mmol) was used as the catalyst and acetic anhydride (40mmol) was used as the solvent. The reaction was heated under reflux. After the reaction was completed, water was added, extracted with ethyl acetate, the organic layers were combined, dried over anhydrous sodium sulfate overnight, and purified by column chromatography. Obtain compound 23f;

Compound 23f, namely 4,2”,2”-trimethyl-3-(4’-fluoro-2’-chlorophenyl)-5-acetoxy-2”H,3”H-6,7- Pyranocoumarin-4"-one: white solid, yield 39%, mp208.5-209.7℃; HR-MS (ESI) m/z: calculated for C ₂₃ H ₁₈ ClFO ₆ [M+H] ⁺ :445.0844, found: 445.0846. ¹ H NMR (500MHz, CDCl ₃ ) δ7.28 (d, J＝8.7Hz, 1H), 7.24-7.18 (m, 1H), 7.10 (t, J＝7.9Hz, 1H) ,6.68(s,1H),2.72(d,J＝4.2Hz,2H),2.42(s,3H,4-CH3),2.40(s,3H,12-CH3),1.56(s,3H,2″ -CH3),1.54(s,3H,2″-CH3). ¹³ CNMR(126MHz,CDCl ₃ )δ189.10,169.25,163.50,161.50,160.53,158.39,152.57,151.07,135.32,132.61,129.49,123.4 6,117.45, 114.79,110.18,109.11,105.41,81.57,48.77,26.63,21.59,21.13.

Step 3. Use methanol as the solvent and compound 23f (8mmol) as the raw material. After heating up and dissolving, place it at 0℃-5℃ for stirring reaction. Add NaBH ₄ (40mmol) dropwise in three times within 1.5h, and add 9-10 times dropwise. Drop 5% HCl into the reaction solution to end the reaction, spin off part of the methanol, extract with ethyl acetate, combine the organic layers, wash with saturated NaHCO ₃ solution, saturated brine, dry over anhydrous sodium sulfate, filter, and recrystallize from methanol. The linear Glycyrrhiza A analogue 3-aryl-6,7-pyranocoumarin 24f was obtained.

Linear Glycyrrhiza A analogue 3-aryl-6,7-pyranocoumarin 24f, i.e. 4,2”,2”-trimethyl-3-(5’-fluoro-3’-chlorophenyl )-5-Hydroxy--2”H,3”H-6,7-pyranocoumarin: white solid, yield 70%, mp271.4-273.5℃; HR-MS (ESI) m/z: calculated for C ₂₁ H ₁₈ ClFO ₅ [M+Na] ⁺ :427.0503, found: 427.0595. ¹ H NMR (500MHz, CDCl ₃ ) δ7.23 (d, J＝7.3Hz, 2H), 7.06 (t, J＝ 8.1Hz,1H),6.79(s,1H),2.71(d,J＝6.1Hz,2H),2.37(s,3H,4-CH ₃ ),1.82(d,J＝6.1Hz,2H),1.39 (s,3H,2″-CH ₃ ),1.37(s,3H,2″-2×CH ₃ ). ¹³ C NMR (126MHz, CDCl ₃ ) δ163.20,161.70,161.21,158.41,153.76,135.73,133.18, 130.58,118.60,116.99,114.52,105.72,104.32,95.10,75.97,31.36,26.90,21.56,16.93.

<Example 7>

A preparation method for 24g of linear Glycyrrhiza A analogue 3-aryl-6,7-pyranocoumarin, including the following steps:

Step 1. 2,4,6-trihydroxyacetophenone (10mmol) and 3,3-dimethacrylic acid (22mmol) are used as raw materials, and anhydrous dioxane is used as the solvent oil bath for heating and reflux reaction. After the reaction is completed , pour ice water, adjust the pH to neutral with saturated potassium carbonate, filter, and separate the crude product by silica gel column chromatography to obtain the white transparent crystal intermediate coumarin 9.

Step 2: Under _N2 gas protection, use intermediate coumarin 9 (1mmol) and 4-bromophenylacetic acid (1mmol) as raw materials, in an acetic anhydride/triethylamine reaction system, use weak base triethylamine (1.5 mmol) as the catalyst and acetic anhydride (40 mmol) as the solvent. The reaction was heated under reflux. After the reaction, water was added, extracted with ethyl acetate, the organic layers were combined, dried over anhydrous sodium sulfate overnight, and purified by column chromatography to obtain 23 g of compound.

Compound 23g, namely 4,2”,2”-trimethyl-3-(4’-bromophenyl)-5-acetoxy-2”H,3”H-6,7-dihydropyranyl aromatic acid Legumin-4"-one: white solid, yield 37%, mp210.2-212.2℃; HR-MS (ESI) m/z: calculated for C ₂₃ H ₁₉ BrO ₆ [M+H] ⁺ :471.0432, found :471.0435. ¹ H NMR (400MHz, CDCl ₃ ) δ7.61 (d, J = 8.4Hz, 2H), 7.16 (d, J = 8.4Hz, 2H), 6.67 (s, 1H), 2.73 (s, 2H) ),2.47(s,3H,4-CH ₃ ),2.42(s,3H,12-CH3),1.55(s,6H,2″-2×CH ₃ ). ¹³ C NMR (126MHz, CDCl3) δ197. 64,163.78,161.67,160.6 8,159.87,150.63,133.39,132.08,131.75,122.42,122.32,104.10,103.89,96.71,79.91,47.79,26.70,26.50,21. 12.

Step 3: Use methanol as the solvent and compound 23g (8mmol) as the raw material. After heating up and dissolving, place it at 0℃-5℃ for stirring reaction. Add NaBH ₄ (44mmol) dropwise in three times within 1.5h, and add 9-10 times dropwise. Drop 5% HCl into the reaction solution to end the reaction, spin dry part of the methanol, extract with ethyl acetate, combine the organic layers, wash with saturated NaHCO3 solution, saturated brine, dry with anhydrous sodium sulfate, filter, and recrystallize with methanol to obtain Linear Glycyrrhiza A analogue 3-aryl-6,7-pyranocoumarin 24g.

Linear Glycyrrhiza A analogue 3-aryl-6,7-pyranocoumarin 24g, i.e. 4,2”,2”-trimethyl-3-(4'-bromophenyl)-5-hydroxy --2”H,3”H-6,7-pyranocoumarin: white solid, yield 70%, mp293.2-294.4℃; HR-MS(ESI)m/z:calculated for C ₂₁ H ₁₉ BrO ₄ [M+H] ⁺ :415.0539found:415.0547; ¹ H NMR (500MHz, CDCl ₃ ) δ7.55 (d, J = 6.8 Hz, 2H), 7.15 (d, J = 6.8 Hz, 2H), 6.72(s,1H),5.26(s,1H,5-OH),2.70(s,2H,2.43(s,3H,4-CH ₃ ),1.82(s,2H),1.38(s,6H,2 ″-2×CH ₃ ). ¹³ CNMR (126MHz, CDCl ₃ ) δ161.09,157.05,153.63,152.79,150.14,134.33,132.22,131.63,122.16,121.96,103.37,98.04,75.03,31.73 ,26.45,21.37,16.63.

<Example 8>

A preparation method of linear Glycyrrhiza A analogue 3-aryl-6,7-pyranocoumarin 24h, including the following steps:

Step 1. 2,4,6-trihydroxyacetophenone (10mmol) and 3,3-dimethacrylic acid (22mmol) are used as raw materials, and anhydrous dioxane is used as the solvent oil bath for heating and reflux reaction. After the reaction is completed , pour ice water, adjust the pH to neutral with saturated potassium carbonate, filter, and separate the crude product by silica gel column chromatography to obtain the white transparent crystal intermediate coumarin 9.

Step 2: Under _N2 gas protection, use intermediate coumarin 9 (1mmol) and 2,4-dichlorophenylacetic acid (1mmol) as raw materials, in an acetic anhydride/triethylamine reaction system, use weak base triethyl Amine was used as the catalyst and acetic anhydride (40 mmol) was used as the solvent. The reaction was heated under reflux. After the reaction, water was added, extracted with ethyl acetate, the organic layers were combined, dried over anhydrous sodium sulfate overnight, and purified by column chromatography to obtain compound 23h.

Compound 23h, i.e. 4,2”,2”-trimethyl-3-(2’,4’-dichlorophenyl)-5-acetoxy-2”H,3”H-6,7-pyridine Coumarin-4"-one: white solid, yield 38%, mp230.5-231.6℃; HR-MS (ESI) m/z: calculated for C ₂₃ H ₁₇ Cl ₂ O ₆ [M+H] ⁺ :461.0550, found: 461.0552. ¹ H NMR (400MHz, CDCl ₃ ) δ7.51 (d, J＝2.0Hz, 1H), 7.33 (dd, J＝8.2, 2.0Hz, 1H), 7.16 (d, J＝ 8.2Hz,1H),6.64(s,1H),2.79(s,2H,),2.36(s,3H,4-CH ₃ ),2.24(s,3H,12-CH ₃ ),1.51(s,6H ,2″-2×CH ₃ ). ¹³ CNMR (101MHz, CDCl ₃ ) δ187.73,168.07,162.48,157.97,154.1,152.80,148.11,135.18,132.48,131.80,129.74,127.59,122.86,10 9.98,107.72,107.23, 81.05,49.89,26.57,26.43,21.50,19.99.

Step 3. Use methanol as the solvent and compound 23h (8mmol) as the raw material. After heating up and dissolving, place it at 0℃-5℃ for stirring reaction. Add NaBH ₄ (40mmol) dropwise in three times within 1.5h, and add 9-10 times dropwise. Drop 5% HCl into the reaction solution to end the reaction, spin off part of the methanol, extract with ethyl acetate, combine the organic layers, wash with saturated NaHCO ₃ solution, saturated brine, dry over anhydrous sodium sulfate, filter, and recrystallize from methanol. The linear Glycyrrhiza A analogue 3-aryl-6,7-pyranocoumarin was obtained for 24 h.

Linear Glycyrrhiza A analogue 3-aryl-6,7-pyranocoumarin 24h, i.e. 4,2”,2”-trimethyl-3-(4'-chlorophenyl)-5-hydroxy --2”H,3”H-6,7-pyranocoumarin: white solid, yield 72%, mp272.6-273.2℃, HR-MS (ESI) m/z: calculated for C ₂₁ H ₁₈ C _l2 O ₄ [M+Na] ⁺ :427.0474, found: 427.0481. ¹ H NMR (500MHz, CDCl3) δ7.51 (s, 1H), 7.32 (d, J = 8.0Hz, 1H), 7.19 (d ,J＝7.7Hz,1H),6.83(s,1H),2.70(t,J＝6.1Hz,2H),2.37(s,3H,4-CH3),1.82(t,J＝6.1Hz,2H) ,1.39(s,6H,2″-2×CH3). ¹³ C NMR(126MHz,CDCl3)δ161.38,158.30,153.95,153.92,153.79,135.67,134.55,133.11,132.96,129.59,127.43,118.57, 105.66,104.32 ,95.08,76.00,31.34,26.67,21.57,16.91.

<Example 9>

A preparation method of linear Glycyrrhiza A analogue 3-aryl-6,7-pyranocoumarin 24i, including the following steps:

Step 1. 2,4,6-trihydroxyacetophenone (10mmol) and 3,3-dimethacrylic acid (22mmol) are used as raw materials, and anhydrous dioxane is used as the solvent oil bath for heating and reflux reaction. After the reaction is completed , pour ice water, adjust the pH to neutral with saturated potassium carbonate, filter, and separate the crude product by silica gel column chromatography to obtain the white transparent crystal intermediate coumarin 9.

Step 2: Under _N2 gas protection, use intermediate coumarin 9 (1mmol) and 2,4,5-trifluorophenylacetic acid (1mmol) as raw materials, in an acetic anhydride/triethylamine reaction system, use a weak base Triethylamine (1.5mmol) was used as the catalyst and acetic anhydride (40mmol) was used as the solvent. The reaction was heated under reflux. After the reaction was completed, water was added, extracted with ethyl acetate, the organic layers were combined, dried over anhydrous sodium sulfate overnight, and purified by column chromatography. Compound 23i was obtained.

Compound 23i, namely 4,2″,2″-trimethyl-3-(2’,4’,5’-trifluorophenyl)-5-acetoxy-2″H,3″H-6, 7-pyranocoumarin-4"-one: white solid, yield 39%, mp174.1-175.5℃; HR-MS (ESI) m/z: calculated for C ₂₃ H ₁₆ F ₃ O ₆ [M +H] ⁺ :447.1049, found: 447.0496. ¹ H NMR (500MHz, CDCl ₃ ) δ7.13 (dd, J＝16.1, 7.7Hz, 1H,), 7.05 (dd, J＝16.1, 7.7Hz, 1H) ,6.67(s,1H),2.73(s,2H),2.48(s,3H,12-CH3),2.41(s,3H,4-CH ₃ ),1.55(s,6H,2″-2×CH ₃ ). ¹³ C NMR (126MHz, CDCl ₃ ) δ189.01,169.14,160.54,158.57,158.28,156.39,154.37,152.84,151.85,147.89,119.95,119.76,118.83,117.90,11 0.29,109.04,105.40,81.71,48.76, 26.46,21.11,14.15.

Step 3. Use methanol as the solvent and compound 23i (8mmol) as the raw material. After heating up and dissolving, place it at 0℃-5℃ for stirring reaction. Add NaBH ₄ (40mmol) dropwise in three times within 1.5h, and add 9-10 times dropwise. Drop 5% HCl into the reaction solution to end the reaction, spin off part of the methanol, extract with ethyl acetate, combine the organic layers, wash with saturated NaHCO ₃ solution, saturated brine, dry over anhydrous sodium sulfate, filter, and recrystallize from methanol. The linear Glycyrrhiza A analogue 3-aryl-6,7-pyranocoumarin 24i was obtained.

Linear Glycyrrhiza A analogue 3-aryl-6,7-pyranocoumarin 24i, i.e. 4,2”,2”-trimethyl-3-(4'-chlorophenyl)-5-hydroxy --2”H,3”H-6,7-pyranocoumarin: white solid, yield 70%, mp280.3-281.8℃, HR-MS (ESI) m/z: calculated for C ₂₁ H ₁₇ F ₃ O ₄ [M+Na] ⁺ :413.0966, found: 413.0972. ¹ H NMR (500MHz, CDCl ₃ ) δ7.12 (dd, J＝16.1, 8.2Hz, 1H), 7.02 (dd, J＝16.2 ,8.1Hz,1H),6.77(s,1H),2.70(t,J＝6.4Hz,2H),2.45(s,3H,4-CH3),1.82(t,J＝6.4Hz,2H),1.39 (s,6H,2″-2×CH3) ¹³ C NMR (126MHz, CDCl3) δ161.36,158.31,154.67,153.98,153.74,149.56,147.76,143.80,120.30,114.08,105.96,105.66,105.57, 104.46,95.00, 76.11,31.30,26.76,21.89,16.89.

<Example 10>

A preparation method for linear Glycyrrhiza A analogue 3-aryl-6,7-pyranocoumarin 24j, including the following steps:

Step 1. 2,4,6-trihydroxyacetophenone (10mmol) and 3,3-dimethacrylic acid (22mmol) are used as raw materials, and anhydrous dioxane is used as the solvent oil bath for heating and reflux reaction. After the reaction is completed , pour ice water, adjust the pH to neutral with saturated potassium carbonate, filter, and separate the crude product by silica gel column chromatography to obtain the white transparent crystal intermediate coumarin 9.

Step 2: Under _N2 gas protection, use intermediate coumarin 9 (1mmol) and bis(trifluoromethyl)phenylacetic acid (1mmol) as raw materials, in an acetic anhydride/triethylamine reaction system, use weak base triethyl Ethylamine (1.5mmol) was used as the catalyst and acetic anhydride (40mmol) was used as the solvent. The reaction was heated under reflux. After the reaction, water was added, extracted with ethyl acetate, the organic layers were combined, dried over anhydrous sodium sulfate overnight, and purified by column chromatography to obtain Compound 23j.

Compound 23j, namely 4,2”,2”-trimethyl-3-(3’,5’-ditrifluoromethylphenyl)-5-acetoxy-2”H,3”H-6, 7-pyranocoumarin-4"-one: white solid, yield 38%, mp140.0-141.8℃; HR-MS (ESI) m/z: calculated for C ₂₅ H ₁₈ F ₆ O ₆ [M +H]+: 529.1080, found: 529.1087. ¹ H NMR (500MHz, CDCl ₃ ) δ7.76 (s, 1H), 7.48 (d, J = 7.2Hz, 2H), 6.78 (s, 1H), 2.70 ( s,2H),2.43(s,3H,12-CH3),2.40(s,3H,4-CH ₃ ),1.43(s,6H,2″-2×CH ₃ ). ¹³ C NMR (126MHz, CDCl ₃ ) δ189.45,169.07,162.5 6,158.75,157.83,149.72,148.89,136.33,132.18,130.69,124.13,122.41,122.01,110.79,108.81,103.90,80.48 ,49.73,26.70,21.63,20.50.

Step 3. Use methanol as the solvent and compound 23j (8mmol) as the raw material. After heating up and dissolving, place it at 0℃-5℃ for stirring reaction. Add NaBH ₄ (40mmol) dropwise in three times within 1.5h, and add 9-10 times dropwise. Drop 5% HCl into the reaction solution to end the reaction, spin off part of the methanol, extract with ethyl acetate, combine the organic layers, wash with saturated NaHCO ₃ solution, saturated brine, dry over anhydrous sodium sulfate, filter, and recrystallize from methanol. The linear Glycyrrhiza A analogue 3-aryl-6,7-pyranocoumarin 24j was obtained.

Linear Glycyrrhiza A analogue 3-aryl-6,7-pyranocoumarin 24j, namely 4,2”,2”-trimethyl-3-(3',5'-bis(trifluoromethyl phenyl)-5-hydroxy-2”H,3”H-6,7-pyranocoumarin: white solid, yield 69%, mp254-255℃, HR-MS (ESI) m/z: calculated for C ₂₃ H ₁₈ F ₆ O ₄ [M+H] ⁺ :473.1109, found: 473.1110. ¹ HNMR (500MHz, CDCl ₃ ) δ7.77 (s, 1H), 7.50 (d, J＝7.2Hz, 2H ),6.77(s,1H),2.43(s,3H,12-CH ₃ ),2.70(t,J＝6.0Hz,2H),2.41(s,3H,4-CH ₃ ),1.97(t,J =6.0Hz,2H),1.40(s,6H,2″-2×CH ₃ ). ¹³ C NMR (126MHz, DMSO) δ160.25,157.66,155.64,153.77,151.78,139.05,132.22,130.47,124.90,122.73, 119.13,105.80,103.31,94.43,76.23,31.14,26.71,22.17,17.21.

<Example 11>

The linear Glycyrrhiza A analogue 3-aryl-6,7-pyranocoumarin prepared in any one of Examples 1-10 is combined with auxiliary materials to prepare injections, tablets, pills, capsules, and suspensions or emulsion. The chemical properties and chemical structure of the linear Glycyrrhiza A analogue 3-aryl-6,7-pyranocoumarin remain stable.

<Example 12>

The linear Glycyrrhiza A analogue 3-aryl-6,7-pyranocoumarin prepared in any one of Examples 1-10 and the auxiliary materials are ethanol, propylene glycol, polyethylene glycol, and diglycerol. Alcohol, triacetin, glycerin, dextrin, povidone, stearyl alcohol, stearic acid, microcrystalline cellulose, starch, lactose, mannitol, sodium bicarbonate, calcium carbonate, low-substituted hydroxypropylmethyl One or more combinations of cellulose, magnesium stearate, and talc can be made into one of injections, tablets, pills, capsules, suspensions or emulsions. The chemical properties of the Glycyrrhiza A derivative, The chemical structure remains stable.

<In vitro anti-tumor activity test>

In vitro anti-tumor screening using MTS method

1) Inoculate cells: Use culture medium (DMEM or RMPI1640) containing 10% fetal bovine serum to prepare a single cell suspension, and inoculate 3,000 to 15,000 cells per well into a 96-well plate. The volume of each well is 100 μl, and the cells are advanced 12 to 12 times. 24 hours inoculation and culture.

2) Add the compound solution to be tested: Dissolve the compounds respectively with DMSO, set the initial concentration to 40 μM, and treat leukocyte HL-60, liver cancer HepG2 tumor cells, cervical cancer HeLa cells, human breast cancer cells MCF-7, and human normal liver cells LO2 respectively. Five types of tumor cells were initially screened, with the final volume of each well being 200 μl, and three duplicate wells for each treatment.

3) Color development: After culturing at 37 degrees Celsius for 48 hours, discard the culture medium in the well and add 20 μl of MTS solution and 100 μl of culture medium to each well; for suspended cells HL-60, discard 100 μl of culture supernatant and add 20 μl of MTS solution to each well. ; Directly add 20 μl of MTS solution to each well of suspended cell MT-4; set up 3 blank duplicate wells (a mixture of 20 μl of MTS solution and 100 μl of culture medium), continue to incubate for 2 to 4 hours, and then measure the light absorption value after the reaction is fully carried out. .

4) Colorimetry: Select the wavelength of 492nm, read the light absorption value of each well with a multifunctional microplate reader (MULTISKAN FC), and record the results. After data processing, the inhibition rate results are obtained as shown in Table 1.

Table 1 IC ₅₀ of linear Glycyrrhiza A analogue 3-aryl-6,7-pyranocoumarin against different tumor cell lines

It can be seen from the results in Table 1 that the in vitro anti-tumor experiments of the linear Glycyrrhiza A analogue 3-aryl-6,7-pyranocoumarin of the present invention show that the compound has strong effects on leukocytes HL-60 and liver cancer HepG2 tumors. cells, cervical cancer HeLa cells, human breast cancer cells MCF-7 and human normal liver cells LO2 have strong anti-tumor activity. The present invention provides new ideas for research and development of new anti-tumor drugs.

Although the embodiments of the present invention have been disclosed above, they are not limited to the applications listed in the description and embodiments. They can be applied to various fields suitable for the present invention. For those familiar with the art, they can easily Additional modifications may be made, and therefore the invention is not limited to the specific details without departing from the general concept defined by the claims and equivalent scope.

Claims (7)

1. Linear Glycyrrhiza A analogue, characterized in that it has the following structural formula I: General formula I is the following compounds 24b-24j; in, 24b: R ₁ =CH ₃ , R ₂ =R ₃ =R ₄ =H; 24c: R ₁ =F, R ₂ =R ₃ =R ₄ =H; 24d: R ₁ =Cl, R ₂ =R ₃ =R ₄ =H; 24e: R ₁ +R ₃ =OCH ₂ O, R ₂ =R ₄ =H; 24f: R ₁ =F, R ₂ =Cl, R ₃ =R ₄ =H; 24g: R ₁ =Br, R ₂ =R ₃ =R ₄ =H; 24h: R ₁ =Cl, R ₂ =Cl, R ₃ =R ₄ =H; 24i: R ₁ =R ₂ =R ₄ =F, R ₃ =H; 24j: R ₁ =R ₂ =H, R ₃ =R ₄ =CF ₃ . 2. The preparation method of the linear Glycyrrhiza A analogue as claimed in claim 1, characterized in that, methanol is used as the solvent, and the compounds 23b-23j are used as the raw materials. After the compounds are heated and dissolved, they are placed at 0°C-5°C for stirring reaction. , add NaBH ₄ dropwise in 2-5 times within 1-3h, add acid solution dropwise to the reaction solution to terminate the reaction, spin off part of the methanol, extract with ethyl acetate, combine the organic layers, and use saturated NaHCO ₃ solution successively to saturated Wash with brine, dry over anhydrous sodium sulfate, filter, and recrystallize from methanol to obtain linear Glycyrrhiza A analogue 3-aryl-6,7-pyranocoumarin 24b-24j; Among them, compounds 23b-23j have the following structural formula II: 23b: R ₁ =CH ₃ , R ₂ =R ₃ =R ₄ =H; 23c: R ₁ =F, R ₂ =R ₃ =R ₄ =H; 23d: R ₁ =Cl, R ₂ =R ₃ =R ₄ =H; 23e: R ₁ +R ₃ =OCH ₂ O, R ₂ =R ₄ =H; 23f: R ₁ =F, R ₂ =Cl, R ₃ =R ₄ =H; 23g: R ₁ =Br, R ₂ =R ₃ =R ₄ =H; 23h: R ₁ =Cl, R ₂ =Cl, R ₃ =R ₄ =H; 23i: R ₁ =R ₂ =R ₄ =F, R ₃ =H; 23j: R ₁ =R ₂ =H, R ₃ =R ₄ =CF ₃ . 3. The preparation method of linear Glycyrrhiza A analogue as claimed in claim 2, characterized in that, under inert gas protection, intermediate coumarin 9 and phenylacetic acid derivatives are used as raw materials, in acetic anhydride/tris In the ethylamine reaction system, use weak base triethylamine as the catalyst and acetic anhydride as the solvent to heat and reflux the reaction. After the reaction is completed, add water, extract with ethyl acetate, combine the organic layers, dry over anhydrous sodium sulfate overnight, and perform column chromatography. Purify to obtain compounds 23b-23j; Among them, the structural formula of intermediate coumarin 9 is: The structural formula of phenylacetic acid derivatives is: In the structural formula: b: R ₁ =CH ₃ , R ₂ =R ₃ =R ₄ =H; c: R ₁ =F, R ₂ =R ₃ =R ₄ =H; d: R ₁ =Cl, R ₂ =R ₃ =R ₄ =H; e: R ₁ +R ₃ =OCH ₂ O, R ₂ =R ₄ =H; f: R ₁ =F, R ₂ =Cl, R ₃ =R ₄ =H; g: R ₁ =Br, R ₂ =R ₃ =R ₄ =H; h: R ₁ =Cl, R ₂ =Cl, R ₃ =R ₄ =H; i: R ₁ =R ₂ =R ₄ =F, R ₃ =H; j: R ₁ =R ₂ =H, R ₃ =R ₄ =CF ₃ . 4. The preparation method of linear Glycyrrhiza A analogue as claimed in claim 3, characterized in that, using 2,4,6-trihydroxyacetophenone and 3,3-dimethacrylic acid as raw materials, Anhydrous dioxane is heated in a solvent oil bath for reflux reaction. After the reaction is completed, pour ice water, adjust the pH to neutral with saturated potassium carbonate, filter, and separate the crude product by silica gel column chromatography to obtain the intermediate coumarin 9. . 5. The use of the linear Glycyrrhiza A analogue as claimed in claim 1, characterized in that the linear Glycyrrhiza A analogue 3-aryl-6,7-pyranocoumarin 24b is used to prepare and inhibit liver cancer. Drugs for HepG2 tumor cells, cervical cancer HeLa cells, human breast cancer cells MCF-7, and human normal liver cells LO2; the linear Glycyrrhiza A analogue 3-aryl-6,7-pyranocoumarin 24c is used for preparation Drugs that inhibit leukocyte HL-60; the linear Glycyrrhiza A analogue 3-aryl-6,7-pyranocoumarin 24d is used to prepare drugs that inhibit leukocyte HL-60, liver cancer HepG2 tumor cells, cervical cancer Hela cells, and human Drugs for normal liver cell LO2; linear Glycyrrhiza A analogue 3-aryl-6,7-pyranocoumarin 24e, 24f, 24h, 24i or 24j is used to prepare and inhibit leukocytes HL-60 and liver cancer HepG2 tumor cells , cervical cancer HeLa cells, human breast cancer cells MCF-7, and human normal liver cell LO2 drugs; linear Glycyrrhiza A analogue 3-aryl-6,7-pyranocoumarin 24g is used to prepare and inhibit liver cancer HepG2 Drugs for tumor cells, cervical cancer HeLa cells, human breast cancer cells MCF-7, and human normal liver cells LO2. 6. The use of the linear Glycyrrhiza A analogue according to claim 5, wherein the linear Glycyrrhiza A analogue is prepared by combining 3-aryl-6,7-pyranocoumarin and auxiliary materials. into injections, tablets, pills, capsules, suspensions or emulsions. 7. The use of the linear Glycyrrhiza A analogue as claimed in claim 6, wherein the auxiliary materials are ethanol, propylene glycol, polyethylene glycol, diethylene glycol, triacetin, glycerol, dextrin, Povidone, stearic acid, stearic acid, microcrystalline cellulose, starch, lactose, mannitol, sodium bicarbonate, calcium carbonate, low-substituted hydroxypropyl methylcellulose, magnesium stearate, talc One or several.