CN117304148A - 3,4-Disubstituted γ-butyrolactone derivatives, preparation methods thereof and applications in preparing anti-tumor drugs - Google Patents

Abstract

The invention discloses a 3, 4-disubstituted gamma-butyrolactone derivative, a preparation method thereof and application of the derivative in preparation of antitumor drugs. The 3, 4-disubstituted gamma-butyrolactone derivative and the preparation method thereof are provided for the first time, and pharmacological test results show that the compound has anti-tumor activity of 10 percentμCan effectively inhibit various solid tumor cell lines under the concentration of M, and has good application prospect in the aspect of preparing novel anticancer drugs.

Description

3,4-Disubstituted γ-butyrolactone derivatives and their preparation methods and anti-tumor preparations Drug application

Technical field

The invention belongs to the field of medicinal chemistry, and specifically relates to 3,4-disubstituted γ-butyrolactone derivatives, their preparation methods and their applications in preparing anti-tumor drugs.

Background technique

Cancer is one of the causes of death worldwide, and its mortality rate has exceeded that of cardiovascular disease. Millions of people die from cancer every year. Currently, the world is facing a severe cancer treatment situation. Globally, with population growth and population aging, the burden of cancer is expected to increase by 50% in 2040 compared with 2020, posing a huge threat to human life and health. Therefore, the effective treatment of cancer is a difficult problem that scientific researchers urgently need to solve and focus on. Currently, surgery, chemotherapy, radiotherapy, immunotherapy and a variety of combined treatments are used clinically to inhibit the development of cancer cells. Among them, chemotherapy refers to the use of chemical drugs to prevent the proliferation and metastasis of tumor cells and ultimately achieve the purpose of killing tumor cells. It is the most common and effective treatment method currently used in clinical applications. However, currently widely used chemotherapy drugs have strong toxic and side effects (such as doxorubicin and cisplatin). It is very critical to find and synthesize new anti-tumor compound structures and develop new anti-tumor drugs.

Contents of the invention

The main purpose of the present invention is to provide a series of 3,4-disubstituted γ-butyrolactone derivatives with tumor cell inhibitory activity and their preparation methods and applications in preparing anti-tumor drugs. Pharmacological tests show that the present invention The compound has the effect of inhibiting the tumor cells of human glioma cell U87 MG, human colon cancer cell HCT-116, and human breast cancer cell MCF-7.

In order to achieve the above object, the first aspect of the present invention is to provide a series of 3,4-disubstituted γ-butyrolactone derivatives with a variety of tumor cell inhibitory activities. The series of 3,4-disubstituted γ-butyrolactone derivatives The chemical structure of γ-butyrolactone derivatives is shown in compound 1-13:

Further, the compounds include compounds 1-13, or pharmaceutically acceptable derivatives and geometric isomers thereof, and salts thereof.

The "pharmaceutically acceptable salts" are sodium salts, potassium salts, calcium salts, etc. formed by compound 1-13; or compound 1-13 forms esters with lysine, arginine, ornithine and then with Hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, and phosphoric acid form corresponding inorganic salts or form corresponding organic acid salts with formic acid, acetic acid, picric acid, methanesulfonic acid, and ethanesulfonic acid; or compounds 1-13 and oxalic acid , malonic acid, succinic acid, fumaric acid, maleic acid, malic acid, tartaric acid, citric acid, aspartic acid or glutamic acid to form esters and then form sodium salts, potassium salts, calcium salts, Aluminum or ammonium salts.

The second aspect of the present invention is to provide an application of a 3,4-disubstituted γ-butyrolactone derivative with tumor cell inhibitory activity. The series of 3,4-disubstituted γ-butyrolactone derivatives are used in tumor cell inhibition. The preferred mammalian patient of the invention is a human, but the invention can be used to treat other mammals as well.

Application of the 3,4-disubstituted γ-butyrolactone derivative in preparing anti-tumor drugs. Cancer-related diseases described in the present invention include: human brain cancer, colon cancer, breast cancer, gastric cancer, cervical cancer and related diseases.

Further, the preparation of the 3,4-disubstituted γ-butyrolactone derivative inhibits human glioma cell U87 MG, human colon cancer cell HCT-116, human breast cancer cell MCF-7, and human gastric cancer cell MGC- 803 and the application of drugs in human cervical cancer cell Hela.

The series of 3,4-disubstituted γ-butyrolactone derivatives are pharmaceutical preparations, consisting of compounds 1-13 or their pharmaceutically acceptable derivatives and geometric isomers and their salts as active ingredients and pharmaceutically acceptable Acceptable excipient composition.

Compounds 1-13 may be formulated in any suitable manner for administration. For example, they may be formulated for topical or inhaled administration, or, more preferably, for oral, transdermal or parenteral administration.

A third aspect of the present invention is to provide a method for preparing a 3,4-disubstituted γ-butyrolactone derivative with tumor cell inhibitory activity, which method includes:

Acetophenones and [hydroxy(p-toluenesulfonyloxy)iodo]benzene are mixed in acetonitrile solvent. After the mixture is heated and refluxed in a 95°C water bath for 1.5 hours, bromoacetic acid and potassium carbonate are added to react for another 2-4 hours. After the reaction, quench with saturated brine, extract with ethyl acetate several times, take the organic phase, concentrate under reduced pressure, and obtain the intermediate product 2-oxo-2-phenylethyl-2-bromoacetic acid by column chromatography. The intermediate product was heated and refluxed at 80°C for about 2 hours in the presence of tetrahydrofuran and triphenylphosphine to obtain 4-phenylfuran-2(5H)-one. Finally, 4-phenylfuran-2(5H)-one and differently substituted benzaldehyde are mixed in methanol, piperidine is used as the reaction catalyst, the reaction is carried out at room temperature for 12-24 hours, and the target product 1-13 is obtained by recrystallization.

The series of 3,4-disubstituted γ-butyrolactone derivatives described in the present invention are obtained through artificial synthesis.

beneficial effects

The 3,4-disubstituted γ-butyrolactone derivative and its preparation method of the present invention are proposed for the first time, and pharmacological test results show that this type of compound has anti-tumor activity.

Compounds 1-13 of the present invention can effectively inhibit various solid tumor cell lines at a concentration of 10 μM, including human glioma cell U87 MG, human colon cancer cell HCT-116, and human breast cancer cell MCF-7. It has good inhibitory activity and can inhibit the proliferation of tumor cells, and is expected to become one of the drugs for cancer treatment.

Detailed ways

The present invention will be further described below in conjunction with specific embodiments. It should be understood that these examples are only used to illustrate the invention and are not intended to limit the scope of the invention. In addition, it should be understood that after reading the content described in the present invention, those skilled in the art can make various changes or modifications to the present invention, and these equivalent forms also fall within the scope defined by the appended claims of this application.

The present invention provides preparation methods and structural identification of compounds 1-13. The raw materials and reagents used in the present invention are all purchased commercially unless otherwise specified.

Identification of compounds by nuclear magnetic resonance ( ¹ H-NMR, ¹³ C-NMR): Weigh about 15 mg of each compound and dissolve it in Acetone-d ₆ (deuterated acetone), CDCl ₃ (deuterated chloroform) or DMSO-d ₆ (deuterated (substitute dimethyl sulfoxide), put the solution into a nuclear magnetic tube, and measure using TMS as the standard reagent.

Example 15 Synthesis of (3-methoxybenzylidene)-4-(4-methoxyphenyl)furan-2(5H)-one (1).

p-Methoxyacetophenone compound (150.18mg, 1mmol) and [hydroxy(p-toluenesulfonyloxy)iodo]benzene (470.30mg, 1.1mmol) were mixed in acetonitrile (10ml) solvent, and the mixture was heated in a 95°C water bath After heating to reflux for 1.5 hours, bromoacetic acid (153.10 mg, 1.1 mmol) and potassium carbonate (180.23 mg, 1.1 mmol) were added and the reaction was continued for 4 hours. After the reaction, quench with saturated brine, extract with ethyl acetate several times, take the organic phase, concentrate under reduced pressure, and obtain the intermediate product 2-oxo-2-phenylethyl-2-bromoacetic acid by column chromatography. The intermediate product was heated and refluxed at 80°C for about 2 hours in the presence of tetrahydrofuran (5 ml) and triphenylphosphine (131.143 mg, 0.5 mmol) to obtain 4-methoxyphenylfuran-2(5H)-one.

Finally, 4-methoxyphenylfuran-2(5H)-one and benzaldehyde (53.06mg, 0.5mmol) were mixed in methanol, piperidine (49.39μL, 0.5mmol) was used as the reaction catalyst, and the reaction was carried out at room temperature for 12- 24h, recrystallization gave a yellow solid, yield 41.21%; ¹ H NMR (400MHz, DMSO-d ₆ ) δ7.82 (s, 2H), 7.64 (d, J = 8.8Hz, 2H), 7.50–7.36 (m ,3H),7.13(d,J＝8.8Hz,2H),6.58(s,1H),6.41(s,1H),3.85(s,3H). ¹³ C NMR (101MHz, DMSO-d ₆ )δ168. 33,161.22,157.73,147.43,133.04,130.54,130.43,129.15,128.85,122.02,114.62,113.20,112.77,55.45.

Example 2 Synthesis of 4-(4-methoxyphenyl)-5-(4-(methylsulfonyl)benzylidene)furan-2(5H)-one (2)

p-Methoxyacetophenone compound (150.18mg, 1mmol) and [hydroxy(p-toluenesulfonyloxy)iodo]benzene (470.30mg, 1.1mmol) were mixed in acetonitrile (10ml) solvent, and the mixture was heated in a 95°C water bath After heating to reflux for 1.5 hours, bromoacetic acid (153.10 mg, 1.1 mmol) and potassium carbonate (180.23 mg, 1.1 mmol) were added and the reaction was continued for 4 hours. After the reaction, quench with saturated brine, extract with ethyl acetate several times, take the organic phase, concentrate under reduced pressure, and obtain the intermediate product 2-oxo-2-phenylethyl-2-bromoacetic acid by column chromatography. The intermediate product was heated and refluxed at 80°C for about 2 hours in the presence of tetrahydrofuran (5 ml) and triphenylphosphine (131.143 mg, 0.5 mmol) to obtain 4-methoxyphenylfuran-2(5H)-one.

Finally, 4-methoxyphenylfuran-2(5H)-one and 4-methanesulfonylbenzaldehyde (92.11 mg, 0.5 mmol) were mixed in methanol, and piperidine (49.39 μL, 0.5 mmol) was used as the reaction catalyst. , reacted at room temperature for 12-24h, and recrystallized to obtain a yellow solid with a yield of 52.31%; ¹ H NMR (400MHz, DMSO-d ₆ ) δ7.93 (d, J = 8.4 Hz, 2H), 7.83 (d, J = 8.8 Hz,2H),7.79(d,J＝8.4Hz,2H),7.09(d,J＝8.9Hz,2H),6.56(d,J＝1.4Hz,1H),5.99(s,1H),5.81( d, J＝5.7Hz, 1H), 3.85 (s, 3H), 3.23 (s, 3H). ¹³ C NMR (101MHz, DMSO-d ₆ ) δ 172.78, 164.78, 161.56, 147.97, 139.67, 129.66, 127.44, 126.54 ,122.59,114.44,113.17,84.39,70.30,55.47,43.59.ESI-MS m/z:357.08[M+H] ⁺ .

Example 35 Synthesis of-(3-methoxybenzylidene)-4-(4-methoxyphenyl)furan-2(5H)-one (3).

p-Methoxyacetophenone compound (150.18mg, 1mmol) and [hydroxy(p-toluenesulfonyloxy)iodo]benzene (470.30mg, 1.1mmol) were mixed in acetonitrile (10ml) solvent, and the mixture was heated in a 95°C water bath After heating to reflux for 1.5 hours, bromoacetic acid (153.10 mg, 1.1 mmol) and potassium carbonate (180.23 mg, 1.1 mmol) were added and the reaction was continued for 4 hours. After the reaction, quench with saturated brine, extract with ethyl acetate several times, take the organic phase, concentrate under reduced pressure, and obtain the intermediate product 2-oxo-2-phenylethyl-2-bromoacetic acid by column chromatography. The intermediate product was heated and refluxed at 80°C for about 2 hours in the presence of tetrahydrofuran (5 ml) and triphenylphosphine (131.143 mg, 0.5 mmol) to obtain 4-methoxyphenylfuran-2(5H)-one.

Finally, 4-methoxyphenylfuran-2(5H)-one and 3-methoxybenzaldehyde (68.07 mg, 0.5 mmol) were mixed in methanol, and piperidine (49.39 μL, 0.5 mmol) was used as the reaction catalyst. , reacted at room temperature for 12-24h, and recrystallized to obtain a yellow solid with a yield of 39.21%; ¹ H NMR (400MHz, DMSO-d ₆ ) δ7.63 (d, J = 8.8 Hz, 2H), 7.47–7.34 (m, 3H) ),7.13(d,J＝8.8Hz,2H),6.57(d,J＝0.7Hz,1H),6.40(s,1H),3.85(s,3H),3.78(s,3H). ¹³ CNMR( 101MHz, DMSO-d ₆ )δ168.26,161.21,159.35,157.73,147.57,134.26,130.43,129.85,122.94,121.99,115.77,114.99,114.61,113.27,112.71,55.44 ,55.15.ESI-MS m/z:309.11[ M+H] ⁺ .

Example 45 Synthesis of-(3,4-dihydroxybenzylidene)-4-(4-methoxyphenyl)furan-2(5H)-one (4).

p-Methoxyacetophenone compound (150.18mg, 1mmol) and [hydroxy(p-toluenesulfonyloxy)iodo]benzene (470.30mg, 1.1mmol) were mixed in acetonitrile (10ml) solvent, and the mixture was heated in a 95°C water bath After heating to reflux for 1.5 hours, bromoacetic acid (153.10 mg, 1.1 mmol) and potassium carbonate (180.23 mg, 1.1 mmol) were added and the reaction was continued for 4 hours. After the reaction, quench with saturated brine, extract with ethyl acetate several times, take the organic phase, concentrate under reduced pressure, and obtain the intermediate product 2-oxo-2-phenylethyl-2-bromoacetic acid by column chromatography. The intermediate product was heated and refluxed at 80°C for about 2 hours in the presence of tetrahydrofuran (5 ml) and triphenylphosphine (131.143 mg, 0.5 mmol) to obtain 4-methoxyphenylfuran-2(5H)-one.

Finally, 4-methoxyphenylfuran-2(5H)-one and 3,4-disubstituted benzaldehyde (69.06 mg, 0.5 mmol) were mixed in methanol, and piperidine (49.39 μL, 0.5 mmol) was used as the reaction catalyst. , reacted at room temperature for 12-24h, recrystallized to obtain a yellow solid, yield 48.67%; ¹ HNMR (400MHz, DMSO-d ₆ ) δ7.59 (d, J = 8.7Hz, 2H), 7.43 (d, J = 2.2Hz) ,1H),7.11(d,J＝8.8Hz,2H),6.78(d,J＝8.3Hz,1H),6.41(s,1H),6.21(s,1H),3.84(s,3H). ¹³ CNMR (101MHz, DMSO-D ₆ ) δ168.66,161.05,157.73,147.57,145.51,145.07,130.32,124.54,124.11,122.35,117.15,115.83,114.57,114.01,111.43,55 .41.ESI-MS m/z:311.09[ M+H] ⁺ .

Example 5 Synthesis of 5-(4-hydroxy-3-methoxybenzylidene)-4-(4-methoxyphenyl)furan-2(5H)-one (5).

p-Methoxyacetophenone compound (150.18mg, 1mmol) and [hydroxy(p-toluenesulfonyloxy)iodo]benzene (470.30mg, 1.1mmol) were mixed in acetonitrile (10ml) solvent, and the mixture was heated in a 95°C water bath After heating to reflux for 1.5 hours, bromoacetic acid (153.10 mg, 1.1 mmol) and potassium carbonate (180.23 mg, 1.1 mmol) were added and the reaction was continued for 4 hours. After the reaction, quench with saturated brine, extract with ethyl acetate several times, take the organic phase, concentrate under reduced pressure, and obtain the intermediate product 2-oxo-2-phenylethyl-2-bromoacetic acid by column chromatography. The intermediate product was heated and refluxed at 80°C for about 2 hours in the presence of tetrahydrofuran (5 ml) and triphenylphosphine (131.143 mg, 0.5 mmol) to obtain 4-methoxyphenylfuran-2(5H)-one.

Finally, 4-methoxyphenylfuran-2(5H)-one and vanillin (76.05mg, 0.5mmol) were mixed in methanol, piperidine (49.39μL, 0.5mmol) was used as the reaction catalyst, and the reaction was carried out at room temperature for 12- 24h, recrystallization gave a yellow solid, yield 48.67%; ¹ H NMR (400MHz, DMSO-d ₆ ) δ9.65 (s, 1H), 7.60 (d, J = 8.9Hz, 2H), 7.45–7.33 (m ,2H),7.12(d,J＝8.9Hz,2H),6.86(d,J＝8.3Hz,1H),6.44(d,J＝0.7Hz,1H),6.33(s,1H),3.85(s ,3H),3.80(s,3H). ¹³ C NMR (101MHz, DMSO-D ₆ )δ168.55,161.06,157.75,148.35,147.62,145.38,130.34,124.71,124.60,122.32,115.94,114.71,114 .57,113.82, 111.60,55.61.ESI-MS m/z:325.10[M+H] ⁺ .

Example 65 Synthesis of-(4-hydroxybenzylidene)-4-(4-methoxyphenyl)furan-2(5H)-one (6).

p-Methoxyacetophenone compound (150.18mg, 1mmol) and [hydroxy(p-toluenesulfonyloxy)iodo]benzene (470.30mg, 1.1mmol) were mixed in acetonitrile (10ml) solvent, and the mixture was heated in a 95°C water bath After heating to reflux for 1.5 hours, bromoacetic acid (153.10 mg, 1.1 mmol) and potassium carbonate (180.23 mg, 1.1 mmol) were added and the reaction was continued for 4 hours. After the reaction, quench with saturated brine, extract with ethyl acetate several times, take the organic phase, concentrate under reduced pressure, and obtain the intermediate product 2-oxo-2-phenylethyl-2-bromoacetic acid by column chromatography. The intermediate product was heated and refluxed at 80°C for about 2 hours in the presence of tetrahydrofuran (5 ml) and triphenylphosphine (131.143 mg, 0.5 mmol) to obtain 4-methoxyphenylfuran-2(5H)-one.

Finally, 4-methoxyphenylfuran-2(5H)-one and p-hydroxybenzaldehyde (61.06 mg, 0.5 mmol) were mixed in methanol, piperidine (49.39 μL, 0.5 mmol) was used as the reaction catalyst, and the reaction was carried out at room temperature. 12-24h, recrystallize to obtain a yellow solid, yield 45.32%; ¹ H NMR (400MHz, DMSO-d ₆ ): ¹ H NMR (400MHz, DMSO-d ₆ ) δ10.02 (s, 1H), 7.69 (d, J＝8.8Hz,2H),7.60(d,J＝8.7Hz,2H),7.11(d,J＝8.8Hz,2H),6.85(d,J＝8.7Hz,2H),6.43(d,J＝ 0.7Hz,1H),6.30(s,1H),3.84(s,3H).; ¹³ CNMR(101MHz,DMSO-d ₆ )δ168.58,161.07,158.78,157.72,145.25,132.62,130.33,124.18,122.30,115.91 ,114.57,113.50,111.62,55.42.ESI-MS m/z:295.31[M+H] ⁺ .

Example 75 Synthesis of (1H-indol-5-yl)methylene)-4-(4-methoxyphenyl)furan-2(5H)-one (7).

p-Methoxyacetophenone compound (150.18mg, 1mmol) and [hydroxy(p-toluenesulfonyloxy)iodo]benzene (470.30mg, 1.1mmol) were mixed in acetonitrile (10ml) solvent, and the mixture was heated in a 95°C water bath After heating to reflux for 1.5 hours, bromoacetic acid (153.10 mg, 1.1 mmol) and potassium carbonate (180.23 mg, 1.1 mmol) were added and the reaction was continued for 4 hours. After the reaction, quench with saturated brine, extract with ethyl acetate several times, take the organic phase, concentrate under reduced pressure, and obtain the intermediate product 2-oxo-2-phenylethyl-2-bromoacetic acid by column chromatography. The intermediate product was heated and refluxed at 80°C for about 2 hours in the presence of tetrahydrofuran (5 ml) and triphenylphosphine (131.143 mg, 0.5 mmol) to obtain 4-methoxyphenylfuran-2(5H)-one.

Finally, 4-methoxyphenylfuran-2(5H)-one and acetaminophen (81.63 mg, 0.5 mmol) were mixed in methanol, and piperidine (49.39 μL, 0.5 mmol) was used as the reaction catalyst at room temperature. React for 12-24 hours and recrystallize to obtain a yellow solid with a yield of 31.72%; ¹ HNMR (400MHz, DMSO-d ₆ ) δ 11.33 (s, 1H), 8.08 (s, 1H), 7.63 (d, J = 8.1Hz) ,3H),7.51–7.39(m,2H),7.13(d,J＝8.2Hz,2H),6.55–6.37(m,3H),3.85(s,3H). ¹³ C NMR(101MHz,DMSO-d ₆ )δ168.79,161.06,157.87,145.17,136.32,130.36,128.07,126.71,124.13,124.07,123.83,122.44,115.47,114.58,111.94,111.38,102.12,5 5.42.ESI-MSm/z:318.11[M+H] ⁺ .

Example 84 Synthesis of (3-(4-methoxyphenyl)-5-oxofuran-2(5H)-ylidene)methyl)phenylacetamide (8).

p-Methoxyacetophenone compound (150.18mg, 1mmol) and [hydroxy(p-toluenesulfonyloxy)iodo]benzene (470.30mg, 1.1mmol) were mixed in acetonitrile (10ml) solvent, and the mixture was heated in a 95°C water bath After heating to reflux for 1.5 hours, bromoacetic acid (153.10 mg, 1.1 mmol) and potassium carbonate (180.23 mg, 1.1 mmol) were added and the reaction was continued for 4 hours. After the reaction, quench with saturated brine, extract with ethyl acetate several times, take the organic phase, concentrate under reduced pressure, and obtain the intermediate product 2-oxo-2-phenylethyl-2-bromoacetic acid by column chromatography. The intermediate product was heated and refluxed at 80°C for about 2 hours in the presence of tetrahydrofuran (5 ml) and triphenylphosphine (131.143 mg, 0.5 mmol) to obtain 4-methoxyphenylfuran-2(5H)-one.

Finally, 4-methoxyphenylfuran-2(5H)-one and acetaminophen (81.63 mg, 0.5 mmol) were mixed in methanol, and piperidine (49.39 μL, 0.5 mmol) was used as the reaction catalyst at room temperature. React for 12-24 hours and recrystallize to obtain a yellow solid with a yield of 41.24%; ¹ HNMR (400MHz, DMSO-d ₆ ) δ 10.15 (s, 1H), 7.77 (d, J = 8.5Hz, 2H), 7.67 (d ,J＝8.6Hz,2H),7.63–7.57(m,2H),7.12(d,J＝8.4Hz,2H),6.50(s,1H),6.33(s,1H),3.85(s,3H) . ¹³ C NMR (101MHz, DMSO-d ₆ ) δ168.63,168.44,161.14,157.69,146.37,140.21,131.40,130.36,127.70,122.15,118.88,114.58,112.79,112.34,55.4 2.ESI-MS m/z:336.12 [M+H] ⁺ .

Example 9 Synthesis of 4-(4-methoxyphenyl)-5-(4-nitrobenzylidene)furan-2(5H)-one (9).

p-Methoxyacetophenone compound (150.18mg, 1mmol) and [hydroxy(p-toluenesulfonyloxy)iodo]benzene (470.30mg, 1.1mmol) were mixed in acetonitrile (10ml) solvent, and the mixture was heated in a 95°C water bath After heating to reflux for 1.5 hours, bromoacetic acid (153.10 mg, 1.1 mmol) and potassium carbonate (180.23 mg, 1.1 mmol) were added and the reaction was continued for 4 hours. After the reaction, quench with saturated brine, extract with ethyl acetate several times, take the organic phase, concentrate under reduced pressure, and obtain the intermediate product 2-oxo-2-phenylethyl-2-bromoacetic acid by column chromatography. The intermediate product was heated and refluxed at 80°C for about 2 hours in the presence of tetrahydrofuran (5 ml) and triphenylphosphine (131.143 mg, 0.5 mmol) to obtain 4-methoxyphenylfuran-2(5H)-one.

Finally, 4-methoxyphenylfuran-2(5H)-one and p-nitrobenzaldehyde (70.56 mg, 0.5 mmol) were mixed in methanol, and piperidine (49.39 μL, 0.5 mmol) was used as the reaction catalyst at room temperature. React for 12-24 hours and recrystallize to obtain a yellow solid with a yield of 41.24%; ¹ HNMR (400MHz, DMSO-d ₆ ) δ8.05 (d, J = 8.5 Hz, 2H), 7.54 (d, J = 8.6 Hz, 2H) ),7.21(d,J＝8.3Hz,2H),7.02(d,J＝8.8Hz,2H),6.07(d,J＝1.2Hz,1H),5.15(s,1H),3.82(s,3H ). ¹³ C NMR (101MHz, DMSO-d ₆ ) δ172.29,164.57,161.54,146.87,145.97,129.49,128.21,122.62,122.47,114.47,113.33,84.49,72.79,55.45.ESI-MS m/z :324.08[ M+H] ⁺ .

Pharmacological tests

Test methods for tumor cell inhibitory activity of compounds

This experiment used the MTT method to evaluate the tumor cell activity of each compound on human glioma cells U87 MG, human colon cancer cells HCT-116, human breast cancer cells MCF-7, human gastric cancer cells MGC-803, and human cervical cancer cells Hela. inhibitory effect. Specific steps are as follows:

Culture U87 MG, HCT-116, MCF-7, MGC-803, and Hela cells to the logarithmic growth phase. After trypsin digestion, they are seeded into a 96-well plate at a density of 3,000 cells/well and placed at 37°C. , incubate overnight in a cell culture incubator with 5% _CO2 . Use DMSO to prepare a 10mM solution of the compound to be tested and a solution of the positive control drug doxorubicin. Use DMEM/RPMI-1640 medium with serum added to dilute the drug to 10μM. After the cells adhere, discard the original medium and add 100 μL of the above-prepared fresh culture medium containing medicine, with 3 duplicate wells for each concentration. After 72 hours of culture, add 10 μL of MTT solution (concentration: 5 mg/mL) to each well. After incubating for 4 hours in a 37°C cell culture incubator, remove the supernatant, add 150 μL of DMSO to each well, and shake for 10 minutes in the dark. After the formazan particles at the bottom of the well are completely dissolved, the absorbance is detected with a microplate reader at a wavelength of 570 nm. The cell viability (Cell viability) is calculated using the following formula:

The calculation formula of cell inhibition rate is as follows:

Cell inhibition rate (%) = 100% - (Cell viability%)

Table 1. Inhibition rates of compounds against various tumor cells

The experimental results are shown in Table 1. The effects of the screened compounds on the activity of various tumor cells at a concentration of 10 μM. Among them, compounds 1, 3, 4, 5, 6, 7, and 12 were detected at a concentration of 10 μM on a variety of tumor cells. The lines (human glioma cell U87 MG, human colon cancer cell HCT-116, human breast cancer cell MCF-7, human gastric cancer cell MGC-803 and human cervical cancer cell Hela) have been characterized with good inhibitory activity (>50% ), especially compound 6 was in a dominant position in this experiment and showed obvious inhibitory effects on a variety of tumor cells. Among them, the inhibitory activity of U87 MG against human glioma cells at a concentration of 10 μM exceeded the positive control drug doxorubicin, so it can be used to prepare anti-human glioma drugs. Comparing the structures of the compounds of the present invention, compounds 1, 3, 4, 5, 6, 7, 8, and 12 contain a para-substituted methoxyphenyl structure directly connected to a furanone. The structure-activity relationship between the molecular structures affects Based on the anti-tumor target and activity intensity of the compound, it is speculated that the para-substituted methoxyphenyl structure directly connected to the furanone may be a necessary structure for this type of compound to have anti-tumor activity.

The above is a description of a series of 3,4-disubstituted γ-butyrolactone derivatives with tumor cell inhibitory activity and a preparation method provided by the present invention. For those skilled in the art, based on the ideas of the embodiments of the present invention , there will be changes in the specific implementation and application scope. In summary, the content of this description should not be understood as a limitation of the present invention.

Claims (5)

1. A 3,4-disubstituted γ-butyrolactone derivative, characterized in that the structure is as follows: 2. Application of the 3,4-disubstituted γ-butyrolactone derivative according to claim 1 for preparing anti-tumor drugs. 3. The application according to claim 2, characterized in that the 3,4-disubstituted γ-butyrolactone derivative is used to prepare drugs for inhibiting human brain cancer, colon cancer, breast cancer, gastric cancer and cervical cancer. . 4. Application according to claim 3, characterized in that the preparation of the 3,4-disubstituted γ-butyrolactone derivative inhibits human glioma cells U87 MG, human colon cancer cells HCT-116, and human breast cancer cells. Application of drugs on cancer cells MCF-7, human gastric cancer cell MGC-803 and human cervical cancer cell Hela. 5. The preparation method of 3,4-disubstituted γ-butyrolactone derivatives according to claim 1, characterized in that it includes the following steps: a. Acetophenones and [hydroxy(p-toluenesulfonyloxy)iodo]benzene are mixed in acetonitrile solvent. After the mixture is heated and refluxed in a 95°C water bath for 1.5 hours, bromoacetic acid and potassium carbonate are added and the reaction is continued for 2-4 Hour; b. After the reaction, quench with saturated brine, extract with ethyl acetate multiple times, take the organic phase, concentrate under reduced pressure, and obtain the intermediate product 2-oxo-2-phenylethyl-2-bromoacetic acid by column chromatography; c. The intermediate product is heated and refluxed at 80°C for about 2 hours in the presence of tetrahydrofuran and triphenylphosphine to obtain 4-phenylfuran-2(5H)-one; d. Mix 4-phenylfuran-2(5H)-one and differently substituted benzaldehyde in methanol, use piperidine as the reaction catalyst, react at room temperature for 12-24 hours, and recrystallize to obtain 3,4-disubstituted γ- Butyrolactone derivatives.