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

Linear type glabra A analogue and preparation and application thereof Download PDF

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CN115197236B
CN115197236B CN202210749248.2A CN202210749248A CN115197236B CN 115197236 B CN115197236 B CN 115197236B CN 202210749248 A CN202210749248 A CN 202210749248A CN 115197236 B CN115197236 B CN 115197236B
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pyranocoumarin
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霍丽妮
陈睿
黄嘉咏
农雅琴
刘晓晨
贾智若
徐浩
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Guangxi University of Chinese Medicine
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Abstract

The invention discloses a linear type licorice A analogue, which has the following structural general formula I:the invention also provides a preparation method of the linear type glabrous greenbrier rhizome A analogue, which takes methanol as a solvent and takes compounds 23a-23j as raw materials, after heating and dissolving, the raw materials are placed in a temperature of 0-5 ℃ for stirring reaction, and NaBH is added dropwise for 2-5 times in 1-3h 4 Dropwise adding 5% HCl solution into the reaction solution to finish the reaction, spinning part of methanol, extracting with ethyl acetate, mixing organic layers, sequentially using saturated NaHCO 3 The solution was washed with saturated saline, dried over anhydrous sodium sulfate, filtered, and recrystallized from methanol to obtain a linear type glabrous greenbrier rhizome a analogue. The linear type glabrous greenbrier rhizome A analogue provided by the invention has strong inhibition effect on white blood cells, lung cancer cells, cervical cancer cells and human breast cancer cells through in vitro anti-tumor experiments.

Description

Linear type glabra A analogue and preparation and application thereof
Technical Field
The invention belongs to the field of medicinal chemistry. More specifically, the invention relates to a glycyrrhiza glabra A analogue 3-aryl-6, 7-pyranocoumarin, and preparation and application thereof.
Background
Cancer is a malignant tumor that originates in epithelial tissue, and cancer cells appear almost anywhere in the body, and these cells grow uncontrolled, spread out to attack surrounding normal tissue, and possibly metastasize to cause tumors to form in multiple parts of the body. According to the report of the world health organization, recently, nearly 1930 ten thousand people are diagnosed as newly increased cancer people worldwide, nearly 1000 ten thousand people die due to cancer, and the mortality rate is far higher than the sum of acquired immune deficiency syndrome and tuberculosis. At present, the main medical treatment means is surgical excision, and in order to better treat cancers, the U.S. food and drug administration approves anticancer drugs such as taxol, vincristine and the like to be marketed, but because of poor targeting selectivity of drug molecules and low bioavailability, normal cells are injured while cancer cells are attacked, so that the patients have side effects such as alopecia, low immunity, emaciation and the like. Therefore, searching for high-efficiency and low-toxicity anticancer drugs becomes one of the hot spots in the scientific research world.
Coumarin (Coumarin) is a compound with a benzopyrone structure, a benzene ring and an alpha-pyrone ring are core components of Coumarin, and due to conformational relation, chemical properties are stable, and more Coumarin analogues can be obtained through the introduction of various functional groups. Coumarin is classified according to basic structure, and can be classified into simple coumarin, furanocoumarin, pyranocoumarin, and other coumarin. Wherein pyranocoumarin derivatives are important components of natural active products, including anticancer, antioxidant, antiinflammatory, and anti-HIV. In recent years. The coumarin extracts a plurality of anticancer active ingredients, and provides a direction for developing new anticancer drugs.
The two Guangdong pterocarpus santalinus (Dalbergia benthamii Prain) is wood vine, and the medicinal part is stem, and is mainly distributed in Guangdong, guangxi, hainan and other places. A linear pyranocoumarin-rhizoma glycyrrhizae A is separated and identified from a Zhuang medicine Santalum album (Dalbergia benthamii Prain), and pharmacological experiments prove that the medicine has obvious effects of eliminating DPpH free radicals and ABTS+ and part free radicals and has a certain inhibition effect on tumor cells. However, the compound has poor water solubility and certain toxicity, and if the compound can be structurally optimized, the water solubility is improved, the toxicity is reduced, and the possibility of using the licorice A derivative as a clinical medicine is improved.
Disclosure of Invention
It is an object of the present invention to solve at least the above problems and to provide at least the advantages to be described later.
The invention takes the totally synthesized intermediate coumarin 9 and phenylacetic acid derivatives as raw materials to synthesize a series of linear type licorice A analogues 3-aryl-6, 7-pyranocoumarin 24a-24j with novel structure, high efficiency and low toxicity.
To achieve these objects and other advantages and in accordance with the purpose of the invention, there is provided a linear type glycyrrhiza glabra a analogue having the following structural formula I:
the general formula I contains compounds 24a-24j;
wherein,,
the preparation method of the linear type glabrous greenbrier rhizome A analogue comprises the steps of taking methanol as a solvent, taking compounds 23a-23j as raw materials, heating for dissolution, placing the mixture at 0-5 ℃ for stirring reaction, and dripping NaBH for 2-5 times in 1-3h 4 Dropwise adding 5% HCl solution into the reaction solution to finish the reaction, spinning part of methanol, extracting with ethyl acetate, mixing organic layers, sequentially using saturated NaHCO 3 Washing the solution with saturated saline, drying with anhydrous sodium sulfate, filtering, recrystallizing with methanol to obtain linear type radix Glycyrrhizae analog 3-aryl-6, 7-pyranocoumarin 24a-24j;
wherein, the compounds 23a-23j have the following structural general formula II:
preferably, under the protection of inert gas, intermediate coumarin 9 and phenylacetic acid derivatives are used as raw materials, weak base triethylamine is used as a catalyst in an acetic anhydride/triethylamine reaction system, acetic anhydride is used as a solvent for heating reflux reaction, water is added after the reaction is finished, ethyl acetate is used for extraction, an organic layer is combined, anhydrous sodium sulfate is dried overnight, and column chromatography is used for purification, so that the compounds 23a-23j are obtained.
Preferably, 2,4, 6-trihydroxyacetophenone and 3, 3-dimethyl acrylic acid are used as raw materials, anhydrous dioxane is used as solvent oil bath for heating reflux reaction, ice water is poured into after the reaction is finished, saturated potassium carbonate is used for regulating pH to be neutral, and filtration is carried out, and crude product silica gel column chromatography is carried out, thus obtaining intermediate coumarin 9.
The application of the linear type glabrous greenbrier rhizome A analogue is that the linear type glabrous greenbrier rhizome A analogue 3-aryl-6, 7-pyranocoumarin is used for preparing an anti-tumor medicament.
Preferably, the linear type glycyrrhiza glabra A analogue 3-aryl-6, 7-pyranocoumarin is combined with auxiliary materials to prepare injection, tablet, pill, capsule, suspending agent or emulsion.
Preferably, the auxiliary materials are one or more of ethanol, propylene glycol, polyethylene glycol, diethylene glycol, glyceryl triacetate, glycerol, dextrin, povidone, stearyl alcohol, stearic acid, microcrystalline cellulose, starch, lactose, mannitol, sodium bicarbonate, calcium carbonate, low-substituted hydroxypropyl methylcellulose, magnesium stearate and talcum powder.
The invention at least comprises the following beneficial effects: the in vitro anti-tumor experiment shows that the linear type glycyrrhiza glabra A analogue 3-aryl-6, 7-pyranocoumarin has strong anti-tumor activity. The preparation method can be applied to preparing antitumor drugs, and can be prepared into common pharmaceutical dosage forms, including injection, tablet, pill, capsule, suspending agent or emulsion.
Additional advantages, objects, and features of the invention will be set forth in part in the description which follows and in part will become apparent to those having ordinary skill in the art upon examination of the following or may be learned from practice of the invention.
Detailed Description
The present invention is described in further detail below to enable those skilled in the art to practice the invention by reference to the specification.
It will be understood that terms, such as "having," "including," and "comprising," as used herein, do not preclude the presence or addition of one or more other elements or groups thereof.
The experimental methods described in the following embodiments are conventional methods unless otherwise indicated, and the reagents and materials are commercially available.
The synthesis route of the linear type glycyrrhiza glabra A analogue 3-aryl-6, 7-pyranocoumarin:
the invention provides a preparation method of the linear type glabrous greenbrier rhizome A analogue, which takes methanol as a solvent, takes compounds 23a-23j (1-10 mmol) as raw materials, heats and dissolves, then carries out stirring reaction at 0-5 ℃ for 2-5 times, and drops NaBH in 1-3h 4 (5-50 mmol) and dropwise adding acid solution such as HCl or sulfuric acid into the reaction solution to complete the reaction, spin-drying part of methanol, extracting with ethyl acetate, mixing organic layers, sequentially using saturated NaHCO 3 Washing the solution with saturated saline, drying with anhydrous sodium sulfate, filtering, recrystallizing with methanol to obtain the linear type radix Glycyrrhizae analog 3-aryl-6, 7-pyranocoumarin 24a-24j.
In one technical scheme, under the protection of inert gas, intermediate coumarin 9 (1-10 mmol) and phenylacetic acid derivative (1-10 mmol) are used as raw materials, weak base triethylamine (0.1-5 mmol) is used as a catalyst in an acetic anhydride/triethylamine reaction system, acetic anhydride (10-100 mmol) is used as a solvent, heating reflux reaction is carried out, water is added after the reaction is finished, ethyl acetate is used for extraction, an organic layer is combined, anhydrous sodium sulfate is dried overnight, and column chromatography purification is carried out to obtain the compounds 23a-23j.
In one technical scheme, 2,4, 6-trihydroxyacetophenone (1-50 mmol) and 3, 3-dimethyl acrylic acid (1-50 mmol) are used as raw materials, anhydrous dioxane is used as solvent oil bath for heating reflux reaction, after the reaction is finished, ice water is poured in, saturated potassium carbonate is used for regulating pH to be neutral, and the crude product is filtered, and silica gel column chromatography is carried out to separate the crude product, thus obtaining the intermediate coumarin 9.
Example 1 ]
A preparation method of a linear type glycyrrhiza glabra A analogue 3-aryl-6, 7-pyranocoumarin 24a comprises the following steps:
step one, 2,4,6, -trihydroxyacetophenone (10 mmol) and 3, 3-dimethyl acrylic acid (22 mmol) are used as raw materials, anhydrous dioxane is used as solvent oil bath for heating reflux reaction, after the reaction is finished, ice water is poured in, saturated potassium carbonate is used for regulating pH to be neutral, and filtration is carried out, thus obtaining the white transparent crystal intermediate coumarin 9 by separating the crude product through silica gel column chromatography.
Step two, N 2 Under the protection of gas, using intermediate coumarin 9 (1 mmol) and p-methyl phenylacetic acid (1 mmol) as raw materials, heating and refluxing in an acetic anhydride/triethylamine reaction system by using weak base triethylamine (1.5 mmol) as a catalyst and acetic anhydride (40 mmol) as a solvent, adding water after the reaction is finished, extracting by using ethyl acetate, combining organic layers, drying by anhydrous sodium sulfate overnight, and purifying by column chromatography to obtain the compound 23a.
Compound 23a, 4,2 "-trimethyl-3-p-methoxyphenyl-5-acetoxy-2" h,3"h-6, 7-pyranocoumarin-4" -one: white single crystal with yield of 30%, m.p.177.2-179.5 ℃; 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 )δ189.73,169.32,161.80,159.75,159.51,157.85,149.10,146.92,131.34,126.77,126.17,114.04,110.46,109.59,103.69,80.15,55.33,49.80,27.23,21.67,20.45.
Step three, taking methanol as a solvent, taking a compound 23a (8 mmol) as a raw material, heating for dissolution, then placing the mixture at 0-5 ℃ for stirring reaction, and dripping NaBH for three times in 1.5h 4 (40 mmol) 9-10 drops of 5% HCl are added dropwise into the reaction solution to finish the reaction, after part of methanol is dried, ethyl acetate is extracted, and thenAnd organic layer, sequentially with saturated NaHCO 3 Washing the solution with saturated saline water, drying with anhydrous sodium sulfate, filtering, recrystallizing with methanol to obtain the linear type radix Glycyrrhizae analog 3-aryl-6, 7-pyranocoumarin.
The linear type gladiolus a analogue 3-aryl-6, 7-pyranocoumarin 24a, namely 4, 2' -trimethyl-3- (p-methoxyphenyl) -5-hydroxy-2 ' H, 3' H-6, 7-pyranocoumarin: orange crystals, yield 70%, m.p.261.4-263.2 ℃; 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＝7.8Hz,2H),6.96(d,J＝7.8Hz,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 a linear type glycyrrhiza glabra A analogue 3-aryl-6, 7-pyranocoumarin 24b comprises the following steps:
step one, 2,4,6, -trihydroxyacetophenone (10 mmol) and 3, 3-dimethyl acrylic acid (22 mmol) are used as raw materials, anhydrous dioxane is used as solvent oil bath for heating reflux reaction, after the reaction is finished, ice water is poured in, saturated potassium carbonate is used for regulating pH to be neutral, and filtration is carried out, thus obtaining the white transparent crystal intermediate coumarin 9 by separating the crude product through silica gel column chromatography.
Step two, N 2 Under the protection of gas, using intermediate coumarin 9 (1 mmol) and p-tolueneacetic acid (1 mmol) as raw materials, heating and refluxing in an acetic anhydride/triethylamine reaction system with weak base triethylamine (1.5 mmol) as a catalyst and acetic anhydride (40 mmol) as a solvent, adding water after the reaction is finished, extracting with ethyl acetate, combining organic layers, drying with anhydrous sodium sulfate overnight, and purifying by column chromatography to obtain the compound 23b.
Compound 23b, 4,2 "-trimethyl-3-p-methylphenyl-5-acetoxy-2" h,3"h-6, 7-pyranocoumarin-4" -one: white colorSolid, yield 31%, m.p.200.2-201.9 ℃; HR-MS (ESI) m/z calculated for C 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 )δ189.28,169.26,160.35,159.81,158.08,152.04,148.71,138.16,131.30,129.87,129.34,126.89,110.07,109.73,105.28,81.33,48.84,26.49,22.10,21.37,21.13.
Step three, taking methanol as a solvent, taking a compound 23b (8 mmol) as a raw material, heating for dissolution, then placing the mixture at 0-5 ℃ for stirring reaction, and dripping NaBH for three times in 1.5h 4 (40 mmol) 9-10 drops of 5% HCl were added dropwise to the reaction mixture to complete the reaction, after spinning down part of the methanol, ethyl acetate was used for extraction, the organic layers were combined and successively saturated NaHCO 3 Washing the solution with saturated saline, drying with anhydrous sodium sulfate, filtering, recrystallizing with methanol to obtain linear type radix Glycyrrhizae analog 3-aryl-6, 7-pyranocoumarin 24b;
the linear type gladiolus a analogue 3-aryl-6, 7-pyranocoumarin 24b, namely 4, 2' -trimethyl-3- (p-methylphenyl) -5-hydroxy-2 ' h, 3' h-6, 7-pyranocoumarin: white solid, yield 69%, m.p.260.0-261.5 ℃; 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 a linear type glycyrrhiza glabra A analogue 3-aryl-6, 7-pyranocoumarin 24c comprises the following steps:
step one, 2,4,6, -trihydroxyacetophenone (10 mmol) and 3, 3-dimethyl acrylic acid (22 mmol) are used as raw materials, anhydrous dioxane is used as solvent oil bath for heating reflux reaction, after the reaction is finished, ice water is poured in, saturated potassium carbonate is used for regulating pH to be neutral, and filtration is carried out, thus obtaining the white transparent crystal intermediate coumarin 9 by separating the crude product through silica gel column chromatography.
Step two, N 2 Under the protection of gas, using intermediate coumarin 9 (1 mmol) and p-fluorophenylacetic acid (1 mmol) as raw materials, heating and refluxing in an acetic anhydride/triethylamine reaction system by using weak base triethylamine (1.5 mmol) as a catalyst and acetic anhydride (40 mmol) as a solvent, adding water after the reaction is finished, extracting by using ethyl acetate, combining organic layers, drying by anhydrous sodium sulfate overnight, and purifying by column chromatography to obtain a compound 23c;
compound 23c, 4,2 "-trimethyl-3-p-fluorophenyl-5-acetoxy-2" h,3"h-6, 7-pyranocoumarin-4" -one: white needle crystals with the yield of 35 percent and m.p.218.1-219.5 ℃; HR-MS (ESI) m/z calculated for C 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 three, taking methanol as a solvent, taking a compound 23c (8 mmol) as a raw material, heating for dissolution, placing the mixture in a condition of stirring at 0-5 ℃ for reaction, and dripping NaBH for three times in 1.5h 4 (40 mmol) 9-10 drops of 5% HCl are added dropwise to the reaction solution to finish the reaction, after part of methanol is dried, ethyl acetate is extracted, the organic layers are combined, and then saturated NaHCO3 solution, saturated saline solution, anhydrous sodium sulfate for drying, filtration and methanol recrystallization are sequentially carried out, so that the linear type glycyrrhiza glabra A analogue 3-aryl-6, 7-pyranocoumarin 24c is obtained.
The linear type gladiolus a analogue 3-aryl-6, 7-pyranocoumarin 24c, namely 4, 2' -trimethyl-3- (p-fluorophenyl) -5-hydroxy-2 ' h, 3' h-6, 7-pyranocoumarin: white solid, yield 72%, m.p.289.5-290.1 ℃; 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 a linear type glycyrrhiza glabra A analogue 3-aryl-6, 7-pyranocoumarin 24d comprises the following steps:
step one, 2,4,6, -trihydroxyacetophenone (10 mmol) and 3, 3-dimethyl acrylic acid (22 mmol) are used as raw materials, anhydrous dioxane is used as solvent oil bath for heating reflux reaction, after the reaction is finished, ice water is poured in, saturated potassium carbonate is used for regulating pH to be neutral, and filtration is carried out, thus obtaining the white transparent crystal intermediate coumarin 9 by separating the crude product through silica gel column chromatography.
Step two, N 2 Under the protection of gas, using intermediate coumarin 9 (1 mmol) and p-chloroacetic acid (22 mmol) as raw materials, using weak base triethylamine as a catalyst in an acetic anhydride/triethylamine reaction system, heating and refluxing with acetic anhydride (40 mmol) as a solvent, adding water after the reaction is finished, extracting with ethyl acetate, combining organic layers, drying anhydrous sodium sulfate overnight, and purifying by column chromatography to obtain the compound 23d.
Compound 23d, 4,2 "-trimethyl-3-p-chlorophenyl-5-acetoxy-2" h,3"h-6, 7-pyranocoumarin-4" -one: white needle crystals with the yield of 34 percent and m.p.230.1-231.2 ℃; HR-MS (ESI) m/z calculated for C 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 )δ189.15,169.21,160.43,159.46,158.08,152.36,149.37,134.40,132.74,131.54,128.92,125.68,110.18,109.48,105.33,81.50,48.80,26.49,22.15,21.13.
Step three, taking methanol as a solvent, taking a compound 23d (8 mmol) as a raw material, heating for dissolution, placing the mixture in a condition of stirring at 0-5 ℃ for reaction, and dripping NaBH for three times in 1.5h 4 (40 mmol) 9-10 drops of 5% HCl were added dropwise to the reaction mixture to complete the reaction, after spinning down part of the methanol, ethyl acetate was used for extraction, the organic layers were combined and successively saturated NaHCO 3 Washing the solution with saturated saline, drying with anhydrous sodium sulfate, filtering, recrystallizing with methanol to obtain the linear type radix Glycyrrhizae analog 3-aryl-6, 7-pyranocoumarin 24d.
The linear type gladiolus a analogue 3-aryl-6, 7-pyranocoumarin 24d, namely 4, 2' -trimethyl-3- (p-chlorophenyl) -5-hydroxy-2 ' H, 3' H-6, 7-pyranocoumarin: white solid, yield 69%, m.p.255.4-256.8 ℃; 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 a linear type glycyrrhiza glabra A analogue 3-aryl-6, 7-pyranocoumarin 24e comprises the following steps:
step one, 2,4,6, -trihydroxyacetophenone (10 mmol) and 3, 3-dimethyl acrylic acid (22 mmol) are used as raw materials, anhydrous dioxane is used as solvent oil bath for heating reflux reaction, after the reaction is finished, ice water is poured in, saturated potassium carbonate is used for regulating pH to be neutral, and filtration is carried out, thus obtaining the white transparent crystal intermediate coumarin 9 by separating the crude product through silica gel column chromatography.
Step two, N 2 Under the protection of gas, using intermediate coumarin 9 (1 mmol) and 3, 4-methylenedioxyphenylacetic acid (1 mmol) as raw materials, heating and refluxing in a reaction system of acetic anhydride/triethylamine by using weak base triethylamine (1.5 mmol) as a catalyst and acetic anhydride (40 mmol) as a solvent, and after the reaction is finishedWater was added, extraction was performed 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, 4,2 "-trimethyl-3- (3 ',4' -methylenedioxyphenyl) -5-acetoxy-2" h,3"h-6, 7-pyranocoumarin-4" -ketone: yellow solid, yield 38%, m.p.233.5-234.2 ℃; 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 three, taking methanol as a solvent, taking a compound 23e (8 mmol) as a raw material, heating for dissolution, placing the mixture in a condition of stirring at 0-5 ℃ for reaction, and dripping NaBH for three times in 1.5h 4 (40 mmol) 9-10 drops of 5% HCl were added dropwise to the reaction mixture to complete the reaction, after spinning down part of the methanol, ethyl acetate was used for extraction, the organic layers were combined and successively saturated NaHCO 3 Washing the solution with saturated saline, drying with anhydrous sodium sulfate, filtering, recrystallizing with methanol to obtain the linear type radix Glycyrrhizae analog 3-aryl-6, 7-pyranocoumarin 24e.
The linear type gladiolus a analogue 3-aryl-6, 7-pyranocoumarin 24e, namely 4, 2' -trimethyl-3- (3 ',4' -methylenedioxyphenyl) -5-hydroxy-2 ' h, 3' h-6, 7-pyranocoumarin: white solid, 71% yield, m.p.253.1-253.8 ℃; 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 a linear type glycyrrhiza glabra A analogue 3-aryl-6, 7-pyranocoumarin 24f comprises the following steps:
step one, 2,4,6, -trihydroxyacetophenone (10 mmol) and 3, 3-dimethyl acrylic acid (22 mmol) are used as raw materials, anhydrous dioxane is used as solvent oil bath for heating reflux reaction, after the reaction is finished, ice water is poured in, saturated potassium carbonate is used for regulating pH to be neutral, and filtration is carried out, thus obtaining the white transparent crystal intermediate coumarin 9 by separating the crude product through silica gel column chromatography.
Step two, N 2 Under the protection of gas, using intermediate coumarin 9 (1 mmol) and 2-chloro-4-fluorophenylacetic acid (1 mmol) as raw materials, heating and refluxing in an acetic anhydride/triethylamine reaction system by using weak base triethylamine (1.5 mmol) as a catalyst and acetic anhydride (40 mmol) as a solvent, adding water after the reaction is finished, extracting by using ethyl acetate, combining organic layers, drying anhydrous sodium sulfate overnight, and purifying by column chromatography to obtain a compound 23f;
compound 23f, 4,2 "-trimethyl-3- (4 '-fluoro-2' -chlorophenyl) -5-acetoxy-2" h,3"h-6, 7-pyranocoumarin-4" -one: white solid, yield 39%, m.p.208.5-209.7 ℃; 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 )δ189.10,169.25,163.50,161.50,160.53,158.39,152.57,151.07,135.32,132.61,129.49,123.46,117.45,114.79,110.18,109.11,105.41,81.57,48.77,26.63,21.59,21.13.
Step three, taking methanol as a solvent, taking a compound 23f (8 mmol) as a raw material, heating for dissolution, placing the mixture in a condition of stirring at 0-5 ℃ for reaction, and dripping NaBH for three times in 1.5h 4 (40 mmol) 9-10 drops of 5% HCl were added dropwise to the reaction mixture to complete the reaction, and after spinning down part of the methanol, ethyl acetate was extracted and combinedOrganic layer, sequentially with saturated NaHCO 3 Washing the solution with saturated saline, drying with anhydrous sodium sulfate, filtering, recrystallizing with methanol to obtain the linear type radix Glycyrrhizae analog 3-aryl-6, 7-pyranocoumarin 24f.
The linear type glycyrrhiza glabra A analogue 3-aryl-6, 7-pyranocoumarin 24f, namely 4, 2' -trimethyl-3- (5 ' -fluoro-3 ' -chlorophenyl) -5-hydroxy-2 ' H, 3' H-6, 7-pyranocoumarin: white solid, yield 70%, m.p.271.4-273.5 ℃; 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 of 24g of linear type glycyrrhiza glabra A analogue 3-aryl-6, 7-pyranocoumarin comprises the following steps:
step one, 2,4,6, -trihydroxyacetophenone (10 mmol) and 3, 3-dimethyl acrylic acid (22 mmol) are used as raw materials, anhydrous dioxane is used as solvent oil bath for heating reflux reaction, after the reaction is finished, ice water is poured in, saturated potassium carbonate is used for regulating pH to be neutral, and filtration is carried out, thus obtaining the white transparent crystal intermediate coumarin 9 by separating the crude product through silica gel column chromatography.
Step two, N 2 Under the protection of gas, using intermediate coumarin 9 (1 mmol) and 4-bromophenylacetic acid (1 mmol) as raw materials, heating and refluxing in an acetic anhydride/triethylamine reaction system by using weak base triethylamine (1.5 mmol) as a catalyst and acetic anhydride (40 mmol) as a solvent, adding water after the reaction is finished, extracting by using ethyl acetate, combining organic layers, drying by anhydrous sodium sulfate overnight, and purifying by column chromatography to obtain 23g of a compound.
23g of compound, i.e. 4,2 "-trimethyl-3- (4' -bromophenyl) -5-acetoxy-2" H,3"H-6, 7-dihydropyran coumarin-4")Ketone: white solid, yield 37%, m.p.210.2-212.2 ℃; 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 three, taking methanol as a solvent, taking 23g (8 mmol) of a compound as a raw material, heating to dissolve, placing the mixture in a condition of stirring at 0-5 ℃ for reaction, and dripping NaBH for three times in 1.5h 4 (44 mmol) 9-10 drops of 5% HCl was added dropwise to the reaction solution to terminate the reaction, after spinning part of methanol, ethyl acetate was extracted, the organic layers were combined, washed successively with saturated NaHCO3 solution, saturated saline solution, dried over anhydrous sodium sulfate, filtered, and recrystallized from methanol to obtain 24g of the linear type Glycyrrhiza glabra A analogue 3-aryl-6, 7-pyranocoumarin.
24g of linear type gladiolus a analogue 3-aryl-6, 7-pyranocoumarin, namely 4,2 '-trimethyl-3- (4' -bromophenyl) -5-hydroxy-2 'H, 3' H-6, 7-pyranocoumarin: white solid, yield 70%, m.p.293.2-294.4 ℃; 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＝6.8Hz,2H),7.15(d,J＝6.8Hz,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 a linear type glycyrrhiza glabra A analogue 3-aryl-6, 7-pyranocoumarin 24h comprises the following steps:
step one, 2,4,6, -trihydroxyacetophenone (10 mmol) and 3, 3-dimethyl acrylic acid (22 mmol) are used as raw materials, anhydrous dioxane is used as solvent oil bath for heating reflux reaction, after the reaction is finished, ice water is poured in, saturated potassium carbonate is used for regulating pH to be neutral, and filtration is carried out, thus obtaining the white transparent crystal intermediate coumarin 9 by separating the crude product through silica gel column chromatography.
Step two, N 2 Under the protection of gas, using intermediate coumarin 9 (1 mmol) and 2, 4-dichlorophenylacetic acid (1 mmol) as raw materials, heating and refluxing in an acetic anhydride/triethylamine reaction system with weak base triethylamine as a catalyst and acetic anhydride (40 mmol) as a solvent, adding water after the reaction is finished, extracting with ethyl acetate, combining organic layers, drying with anhydrous sodium sulfate overnight, and purifying by column chromatography to obtain the compound 23h.
Compound 23h, 4,2 "-trimethyl-3- (2 ',4' -dichlorophenyl) -5-acetoxy-2" h,3"h-6, 7-pyranocoumarin-4" -ketone: white solid, yield 38%, m.p.230.5-231.6 ℃; 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 )δ187.73,168.07,162.48,157.97,154.1,152.80,148.11,135.18,132.48,131.80,129.74,127.59,122.86,109.98,107.72,107.23,81.05,49.89,26.57,26.43,21.50,19.99.
Step three, taking methanol as a solvent, taking a compound 23h (8 mmol) as a raw material, heating for dissolving, placing the mixture in a temperature range of 0-5 ℃ for stirring reaction, and dripping NaBH for three times in 1.5h 4 (40 mmol) 9-10 drops of 5% HCl were added dropwise to the reaction mixture to complete the reaction, after spinning down part of the methanol, ethyl acetate was used for extraction, the organic layers were combined and successively saturated NaHCO 3 Washing the solution with saturated saline water, drying with anhydrous sodium sulfate, filtering, recrystallizing with methanol to obtain the linear type radix Glycyrrhizae analog 3-aryl-6, 7-pyranocoumarin for 24h.
The linear type glycyrrhiza glabra A analogue 3-aryl-6, 7-pyranocoumarin is 24h, namely 4,2 '-trimethyl-3- (4' -chlorophenyl) -5-hydroxy-2 'H, 3' H-6, 7-pyranocoumarin: a white solid was used as a solid,yield 72%, m.p.272.6-273.2 ℃, 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 a linear type glycyrrhiza glabra A analogue 3-aryl-6, 7-pyranocoumarin 24i comprises the following steps:
step one, 2,4,6, -trihydroxyacetophenone (10 mmol) and 3, 3-dimethyl acrylic acid (22 mmol) are used as raw materials, anhydrous dioxane is used as solvent oil bath for heating reflux reaction, after the reaction is finished, ice water is poured in, saturated potassium carbonate is used for regulating pH to be neutral, and filtration is carried out, thus obtaining the white transparent crystal intermediate coumarin 9 by separating the crude product through silica gel column chromatography.
Step two, N 2 Under the protection of gas, using intermediate coumarin 9 (1 mmol) and 2,4, 5-trifluoro phenylacetic acid (1 mmol) as raw materials, heating and refluxing in an acetic anhydride/triethylamine reaction system by using weak base triethylamine (1.5 mmol) as a catalyst and acetic anhydride (40 mmol) as a solvent, adding water after the reaction is finished, extracting by ethyl acetate, combining organic layers, drying by anhydrous sodium sulfate overnight, and purifying by column chromatography to obtain the compound 23i.
Compound 23i, 4,2 "-trimethyl-3- (2 ',4',5' -trifluorophenyl) -5-acetoxy-2" h,3"h-6, 7-pyranocoumarin-4" -one: white solid, 39% yield, m.p.174.1-175.5 ℃; 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 )δ189.01,169.14,160.54,158.57,158.28,156.39,154.37,152.84,151.85,147.89,119.95,119.76,118.83,117.90,110.29,109.04,105.40,81.71,48.76,26.46,21.11,14.15.
Step three, taking methanol as a solvent, taking a compound 23i (8 mmol) as a raw material, heating for dissolution, placing the mixture in a condition of stirring at 0-5 ℃ for reaction, and dripping NaBH for three times in 1.5h 4 (40 mmol) 9-10 drops of 5% HCl were added dropwise to the reaction mixture to complete the reaction, after spinning down part of the methanol, ethyl acetate was used for extraction, the organic layers were combined and successively saturated NaHCO 3 Washing the solution with saturated saline, drying with anhydrous sodium sulfate, filtering, recrystallizing with methanol to obtain the linear type radix Glycyrrhizae analog 3-aryl-6, 7-pyranocoumarin 24i.
The linear type glycyrrhiza glabra A analogue 3-aryl-6, 7-pyranocoumarin 24i is 4,2 '-trimethyl-3- (4' -chlorophenyl) -5-hydroxy-2 'H, 3' H-6, 7-pyranocoumarin: white solid, 70% yield, m.p.280.3-281.8 ℃, 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 of a linear type glycyrrhiza glabra A analogue 3-aryl-6, 7-pyranocoumarin 24j comprises the following steps:
step one, 2,4,6, -trihydroxyacetophenone (10 mmol) and 3, 3-dimethyl acrylic acid (22 mmol) are used as raw materials, anhydrous dioxane is used as solvent oil bath for heating reflux reaction, after the reaction is finished, ice water is poured in, saturated potassium carbonate is used for regulating pH to be neutral, and filtration is carried out, thus obtaining the white transparent crystal intermediate coumarin 9 by separating the crude product through silica gel column chromatography.
Step two, N 2 Under the protection of gas, using intermediate coumarin 9 (1 mmol) and bis (trifluoromethyl) phenylacetic acid (1 mmol) as raw materials, and adding acetic anhydrideIn a triethylamine reaction system, weak base triethylamine (1.5 mmol) is used as a catalyst, acetic anhydride (40 mmol) is used as a solvent for heating reflux reaction, after the reaction is finished, water is added, ethyl acetate is used for extraction, an organic layer is combined, anhydrous sodium sulfate is dried overnight, and column chromatography is used for purification, so that the compound 23j is obtained.
Compound 23j, i.e. 4,2 "-trimethyl-3- (3 ',5' -bistrifluoromethylphenyl) -5-acetoxy-2" h,3"h-6, 7-pyranocoumarin-4" -ketone: white solid, yield 38%, m.p.140.0-141.8 ℃; 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 three, taking methanol as a solvent, taking a compound 23j (8 mmol) as a raw material, heating for dissolution, placing the mixture in a condition of stirring at 0-5 ℃ for reaction, and dripping NaBH for three times in 1.5h 4 (40 mmol) 9-10 drops of 5% HCl were added dropwise to the reaction mixture to complete the reaction, after spinning down part of the methanol, ethyl acetate was used for extraction, the organic layers were combined and successively saturated NaHCO 3 Washing the solution with saturated saline, drying with anhydrous sodium sulfate, filtering, recrystallizing with methanol to obtain the linear type radix Glycyrrhizae analog 3-aryl-6, 7-pyranocoumarin 24j.
Linear type Glycyrrhiza glabra A analogue 3-aryl-6, 7-pyranocoumarin 24j, i.e. 4, 2' -trimethyl-3- (3 ',5' -bis (trifluoromethylphenyl) -5-hydroxy-2 ' H, 3' H-6, 7-pyranocoumarin: white solid with yield 69%, m.p.254-255 ℃, HR-MS (ESI) m/z: calculated for C 23 H 18 F 6 O 4 [M+H] + :473.1109,found:473.1110. 1 H NMR(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 type glycyrrhiza glabra A analogue 3-aryl-6, 7-pyranocoumarin prepared in any one of embodiments 1-10 is combined with auxiliary materials to prepare injection, tablet, pill, capsule, suspending agent or emulsion. The chemical property and chemical structure of the linear type glycyrrhiza glabra A analogue 3-aryl-6, 7-pyranocoumarin are kept stable.
Example 12 ]
The linear type licorice A analogue 3-aryl-6, 7-pyranocoumarin prepared in any one of the embodiments 1-10 and the auxiliary materials are one or more of ethanol, propylene glycol, polyethylene glycol, diethylene glycol, glyceryl triacetate, glycerol, dextrin, povidone, stearyl alcohol, stearic acid, microcrystalline cellulose, starch, lactose, mannitol, sodium bicarbonate, calcium carbonate, low-substituted hydroxypropyl methyl cellulose, magnesium stearate and talcum powder, and the linear type licorice A analogue is prepared into one of injection, tablet, pill, capsule, suspending agent or emulsion, wherein the chemical property and chemical structure of the licorice A derivative are kept stable.
< in vitro anti-tumor Activity experiment >
In vitro antitumor screening using MTS method
1) Inoculating cells: single cell suspension is prepared by culture solution (DMEM or RMPI 1640) containing 10% fetal bovine serum, 3000-15000 cells are inoculated into a 96-well plate, the volume of each well is 100 mu l, and the cells are inoculated and cultured in advance for 12-24 hours.
2) Adding a solution of a compound to be tested: the compound is dissolved by DMSO respectively, the initial concentration is set to 40 mu M, five tumor cells of leucocyte HL-60, liver cancer HepG2 tumor cell, cervical cancer Hela cell, human breast cancer cell MCF-7 and human normal liver cell LO2 are screened respectively, the final volume of each hole is 200 mu l, and 3 compound holes are arranged in each treatment.
3) Color development: after culturing at 37 ℃ for 48 hours, removing culture solution in the wells of the adherent cells, and adding 20 mu l of MTS solution and 100 mu l of culture solution into each well; suspension cells HL-60 were discarded with 100. Mu.l of culture supernatant and 20. Mu.l of MTS solution was added to each well; suspension cells MT-4 were directly added with 20. Mu.l MTS solution per well; 3 blank wells (mixed solution of 20. Mu.l MTS solution and 100. Mu.l culture solution) were used, and incubation was continued for 2 to 4 hours to allow the reaction to proceed sufficiently, and then the light absorption value was measured.
4) Colorimetric: the light absorption values of each well were read by a multifunctional microplate reader (MULTISKAN FC) at a wavelength of 492nm, and the results were recorded, and after data processing, inhibition results were obtained as shown in Table 1.
TABLE 1 IC of Linear Glycyrrhiza glabra A analog 3-aryl-6, 7-pyranocoumarin for different tumor cell lines 50
From the results shown in Table 1, the in vitro anti-tumor experiment shows that the linear type glabrous greenbrier rhizome A analogue 3-aryl-6, 7-pyranocoumarin has strong anti-tumor activity on leucocyte HL-60, liver cancer HepG2 tumor cell, cervical cancer Hea cell, human breast cancer cell MCF-7 and human normal liver cell LO 2. The invention provides a new thought for researching and developing new anti-tumor drugs.
Although embodiments of the present invention have been disclosed above, it is not limited to the use of the description and embodiments, it is well suited to various fields of use for the invention, and further modifications may be readily apparent to those skilled in the art, and accordingly, the invention is not limited to the particular details without departing from the general concepts defined in the claims and the equivalents thereof.

Claims (7)

1. The linear type licorice A analogue is characterized by having the following structural general formula I:
the general formula I is the following compounds 24b-24j;
wherein,,
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 method for preparing linear type glabrous greenbrier rhizome A analogue as claimed in claim 1, wherein methanol is used as a solvent, the compound 23b-23j is used as a raw material, after heating and dissolving, the mixture is stirred and reacted at 0-5 ℃ for 2-5 times in 1-3 hours, and NaBH is added dropwise 4 Dropwise adding acid solution into the reaction solution to finish the reaction, spin-drying part of methanol, extracting with ethyl acetate, mixing organic layers, sequentially using saturated NaHCO 3 Washing the solution with saturated saline, drying with anhydrous sodium sulfate, filtering, recrystallizing with methanol to obtain linear type radix Glycyrrhizae analog A, 3-aryl-6, 7-pyranocoumarin 24b-24j;
wherein, the compounds 23b-23j have the following structural general 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 method for preparing the linear type glabrous greenbrier rhizome A analogue according to claim 2, which is characterized in that under the protection of inert gas, intermediate coumarin 9 and phenylacetic acid derivatives are used as raw materials, weak base triethylamine is used as a catalyst in an acetic anhydride/triethylamine reaction system, acetic anhydride is used as a solvent for heating reflux reaction, after the reaction is finished, water is added, ethyl acetate is used for extraction, an organic layer is combined, anhydrous sodium sulfate is dried overnight, and the compound 23b-23j is obtained through column chromatography purification;
wherein, the structural formula of the intermediate coumarin 9 is as follows:
the structural formula of the phenylacetic acid derivative is as follows:
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 method for preparing the linear type glabrous greenbrier rhizome A analogue according to claim 3, which is characterized in that 2,4, 6-trihydroxy acetophenone and 3, 3-dimethyl acrylic acid are used as raw materials, anhydrous dioxane is used as solvent oil bath for heating reflux reaction, after the reaction is finished, ice water is poured in, saturated potassium carbonate is used for regulating the pH value to be neutral, and the crude product is filtered, and silica gel column chromatography is carried out to separate the crude product, thus obtaining the intermediate coumarin 9.
5. The use of the linear type gladiolus a analogue according to claim 1, wherein the linear type gladiolus a analogue 3-aryl-6, 7-pyranocoumarin 24b is used for preparing a medicament for inhibiting liver cancer HepG2 tumor cells, cervical cancer Hela cells, human breast cancer cells MCF-7, human normal liver cells LO 2; the linear type glycyrrhiza glabra A analogue 3-aryl-6, 7-pyranocoumarin 24c is used for preparing medicines for inhibiting leucocyte HL-60; the linear type glabrous greenbrier rhizome A analogue 3-aryl-6, 7-pyranocoumarin 24d is used for preparing medicines for inhibiting leucocyte HL-60, liver cancer HepG2 tumor cells, cervical cancer HeLa cells and human normal liver cell LO 2; the linear type glabrous greenbrier rhizome A analogue 3-aryl-6, 7-pyranocoumarin 24e, 24f, 24h, 24i or 24j is used for preparing medicines for inhibiting leucocyte HL-60, liver cancer HepG2 tumor cell, cervical cancer Hea cell, human breast cancer cell MCF-7 and human normal liver cell LO 2; the linear type glabrous greenbrier rhizome A analogue 3-aryl-6, 7-pyranocoumarin 24g is used for preparing medicaments for inhibiting liver cancer HepG2 tumor cells, cervical cancer Hela cells, human breast cancer cells MCF-7 and human normal liver cells LO 2.
6. The use of the linear type gladiolus a analogue according to claim 5, wherein the linear type gladiolus a analogue 3-aryl-6, 7-pyranocoumarin is combined with auxiliary materials to prepare injection, tablet, pill, capsule, suspending agent or emulsion.
7. The use of the linear type glabrous greenbrier rhizome A analogue as claimed in claim 6, wherein the auxiliary material is one or more of ethanol, propylene glycol, polyethylene glycol, diethylene glycol, glyceryl triacetate, glycerol, dextrin, povidone, stearyl alcohol, stearic acid, microcrystalline cellulose, starch, lactose, mannitol, sodium bicarbonate, calcium carbonate, low-substituted hydroxypropyl methyl cellulose, magnesium stearate and talcum powder.
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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1990008529A2 (en) * 1989-01-23 1990-08-09 Lehigh University 7-alkoxycoumarins, dihydropsoralens, and benzodipyranones as photo-activated therapeutic agents and inhibitors of epidermal growth factor
CN104341430A (en) * 2014-09-30 2015-02-11 广西中医药大学 3-phenylcoumarin robustic acid as well as extraction method and application thereof
CN111217825A (en) * 2020-02-25 2020-06-02 广西中医药大学 4-O-aminopropyl earth licorice A derivative and preparation and application thereof

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1990008529A2 (en) * 1989-01-23 1990-08-09 Lehigh University 7-alkoxycoumarins, dihydropsoralens, and benzodipyranones as photo-activated therapeutic agents and inhibitors of epidermal growth factor
CN104341430A (en) * 2014-09-30 2015-02-11 广西中医药大学 3-phenylcoumarin robustic acid as well as extraction method and application thereof
CN111217825A (en) * 2020-02-25 2020-06-02 广西中医药大学 4-O-aminopropyl earth licorice A derivative and preparation and application thereof

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