4-sydnone substituted phenyl epipodophyllotoxin derivative and preparation method and application thereof

A technology of epipodophyllotoxin and sterone, which is applied in the fields of 4-sterone substituted anilino-epipodophyllotoxin derivatives and the fields of preparation and application thereof, and can solve the problems of unstopped podophyllotoxin and the like

Inactive Publication Date: 2014-03-26
TIANJIN POLYTECHNIC UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

At present, researchers at home and abroad are still working on the structural modification of podophyllotoxin

Method used

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  • 4-sydnone substituted phenyl epipodophyllotoxin derivative and preparation method and application thereof
  • 4-sydnone substituted phenyl epipodophyllotoxin derivative and preparation method and application thereof
  • 4-sydnone substituted phenyl epipodophyllotoxin derivative and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0019] Synthesis of Compound 10a:

[0020] Compound 5 is prepared from compound 1 by the method of literature (Org.Commun., 2010, 30). Compound 5 can be prepared into compound 6 with various structures through acylation, halogenation, sulfonylation and other reactions.

[0021] Compound 9 was prepared from compound 7 by the method of literature (Chem.Pharm.Bull., 2008, 831-834).

[0022] Dissolve 0.42g (1.0mmol) of 4-amino-4-deoxy-4'-demethylepipodophyllotoxin (9) in 10mL of tetrahydrofuran with stirring, and cool the reaction solution to 0°C in an ice bath. At this temperature, 0.40 g (2.0 mmol) of barium carbonate and 0.36 g (1.5 mmol) of compound 5 were added to the reaction flask, the ice bath was removed, and the reaction was stirred at room temperature for 10 h under nitrogen protection. After completion of the reaction, filter with suction, add 20 mL of water to the filtrate, extract with ethyl acetate, dry over anhydrous sodium sulfate, and concentrate the solvent und...

Embodiment 2

[0024] Synthesis of Compound 10b:

[0025] Compound 6b was prepared from compound 5 by the method of literature (Heterocycles, 2008, 91).

[0026] Dissolve 0.42g (1.0mmol) of 4-amino-4-deoxy-4'-demethylepipodophyllotoxin (9) in 10mL of tetrahydrofuran with stirring, and cool the reaction solution to 0°C in an ice bath. At this temperature, 0.40 g (2.0 mmol) of barium carbonate and 0.43 g (1.5 mmol) of compound 6b were added to the reaction flask, the ice bath was removed, and under the protection of nitrogen, the reaction was stirred at room temperature for 10 h. After completion of the reaction, filter with suction, add 20 mL of water to the filtrate, extract with ethyl acetate, dry over anhydrous sodium sulfate, and concentrate the solvent under reduced pressure to obtain a crude product, which is purified by column chromatography (petroleum ether-ethyl acetate gradient elution) to obtain the product, the product is Pale yellow solid, yield 63%; Mp192-194°C (d); -86.0 (c=...

experiment example

[0028] Experimental example: the compound designed by the present invention has inhibitory effect on tumor cells

[0029] Method: Using MTT method

[0030] The in vitro anti-tumor activity of the target compound on HeLa cells (human cervical cancer cells, Henrietta Lacks cancer cell line) and SKOV3 cells (human ovarian cancer cells, ovarian epithelial carcinoma cell line) was tested by MTT (thiazolium blue) method. The test results are shown in Table 1, and the values ​​in the table are average values ​​of three times (n=3). The results of the activity test show that the synthesized compound has in vitro activity against two kinds of human tumor cells, and this type of compound has the value of further research.

[0031] The in vitro antitumor activity of table 1 compound 10a and 10b

[0032]

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PUM

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Abstract

The invention discloses a 4-sydnone substituted phenyl epipodophyllotoxin derivative and a preparation method and application of compounds thereof. The invention additionally relates to salts formed by physiologically acceptable and chemically formable inorganic acid or organic acid of the compounds. The compounds provided by the invention can be applied to formulas of anti-tumor drugs. The structural general formula of the compounds provided by the invention is as shown by the accompanying drawing.

Description

technical field [0001] The invention belongs to the patent of compound preparation and application, and mainly relates to new 4-sydrone substituted aniline epipodophyllotoxin derivatives and their application in the treatment of tumors. The invention also relates to the physiologically acceptable and chemical Salts of inorganic or organic acids that can be formed above. Background technique [0002] The natural product Podophyllotoxin and its derivatives have strong and extensive anti-tumor activities. They produce cytotoxic activity by acting on tubulin or DNA topoisomerase II, thereby exerting anti-tumor effects. However, the large toxic and side effects of podophyllotoxin itself limit its application in tumor therapy, and people have developed etoposide (Etoposide) and teniposide (Teniposide), two clinically used broad-spectrum anticancer drugs. Semi-synthetic podophyllotoxin anti-tumor drugs with tumor effects, but these two drugs have the disadvantages of poor bioavail...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D493/04A61P35/00
CPCC07D493/04
Inventor 于鹏飞王兵臧洪俊郑春明白锁城韦秋丽王卓
Owner TIANJIN POLYTECHNIC UNIV
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