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Cisplatin-flurbiprofen prodrug, as well as preparation method and application thereof

A flurbiprofen and cisplatin technology, applied in the field of chemical prodrugs and their preparation, can solve the problems of not reversing drug resistance, unable to more effectively improve drug treatment effect, etc., and achieve the effect of enhancing anti-tumor effect

Active Publication Date: 2017-12-08
THE NAT CENT FOR NANOSCI & TECH NCNST OF CHINA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the methods disclosed above do not have the effect of reversing drug resistance, and cannot improve the effect of drug treatment more effectively.

Method used

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  • Cisplatin-flurbiprofen prodrug, as well as preparation method and application thereof
  • Cisplatin-flurbiprofen prodrug, as well as preparation method and application thereof
  • Cisplatin-flurbiprofen prodrug, as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0035] This example prepares cisplatin-flurbiprofen prodrug by the method comprising following steps.

[0036] (1) Add 1005.94mg (4.12mmol) flurbiprofen in the three-necked flask, pass N 2 half an hour.

[0037] (2) Add oxalyl chloride into the three-necked flask (so that the molar ratio of flurbiprofen to oxalyl chloride is 1:10), heat up to 70°C, heat, stir, and reflux for 1 hour, and cool to room temperature to obtain a yellow transparent liquid.

[0038] (3) Transfer the yellow transparent liquid obtained in step (2) to an eggplant-shaped bottle, and remove the oxalyl chloride by rotary evaporation to obtain a yellow oily liquid; add 6 mL of anhydrous tetrahydrofuran (THF), and remove it by rotary evaporation; repeat this step twice .

[0039] (4) Add 69.3mg (0.207mmol) dichlorodihydroxydiammine platinum (Pt(NH 3 ) 2 (OH) 2 Cl 2), 6mL tetrahydrofuran (THF), under the condition of avoiding light, heat up to 70°C, heat, stir, and reflux for 2h, a light yellow precipita...

Embodiment 2

[0047] This example prepares cisplatin-flurbiprofen prodrug by the method comprising following steps.

[0048] (1) Add 1005.94mg (4.12mmol) flurbiprofen in the three-necked flask, pass N 2 half an hour.

[0049] (2) Add oxalyl chloride into the three-necked flask (so that the molar ratio of flurbiprofen to oxalyl chloride is 1:20), heat up to 70°C, heat, stir, and reflux for 2 hours, and cool to room temperature to obtain a yellow transparent liquid.

[0050] (3) Transfer the yellow transparent liquid obtained in step (2) to an eggplant-shaped bottle, and remove the oxalyl chloride by rotary evaporation to obtain a yellow oily liquid; add 5 mL of tetrahydrofuran (THF), and remove it by rotary evaporation; repeat this step twice.

[0051] (4) Add 46.0mg (0.137mmol) dichlorodihydroxydiammine platinum (Pt(NH 3 ) 2 (OH) 2 Cl 2 ), 6mL tetrahydrofuran (THF), under the condition of avoiding light, the temperature was raised to 70°C, heated, stirred, and refluxed for 3h, a light ...

Embodiment 3

[0057] This example prepares cisplatin-flurbiprofen prodrug by the method comprising following steps.

[0058] (1) Add 1005.94mg (4.12mmol) flurbiprofen in the three-necked flask, pass N 2 half an hour.

[0059] (2) Add oxalyl chloride into the three-necked flask (so that the molar ratio of flurbiprofen to oxalyl chloride is 1:4), heat up to 50°C, heat, stir, and reflux for 0.5h, and cool to room temperature to obtain a yellow transparent liquid.

[0060] (3) Transfer the yellow transparent liquid obtained in step (2) to an eggplant-shaped bottle, and remove the oxalyl chloride by rotary evaporation to obtain a yellow oily liquid; add 6 mL of tetrahydrofuran (THF), and remove by rotary evaporation; repeat this step twice.

[0061] (4) Add 138.6mg (0.414mmol) dichlorodihydroxydiammine platinum (Pt(NH 3 ) 2 (OH) 2 Cl 2 ), 6mL tetrahydrofuran (THF), under the condition of avoiding light, heat up to 50°C, heat and stir for 1h, a light yellow precipitate is obtained in the bot...

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Abstract

The invention provides a cisplatin-flurbiprofen prodrug, as well as a preparation method and application thereof. The cisplatin-flurbiprofen prodrug is a tetravalent platinum prodrug, and an anti-inflammatory drug flurbiprofen is connected to the two axial positions of tetravalent platinum. The preparation method of the cisplatin-flurbiprofen prodrug comprises the following steps: (1) enabling the flurbiprofen to react with oxalyl chloride to obtain flurbilofenyl chloride; (2) enabling the flurbilofenyl chloride to react with dihydroxyl diamineplatinum dichloride to obtain the cisplatin-flurbiprofen prodrug. The prepared cisplatin-flurbiprofen prodrug can be reduced by a reducing molecular such as glutathione in a cell in a cellular environment to release monomolecular cisplatin and bimolecular flurbiprofen, DNAs (deoxyribonucleic acids) are damaged by the cisplatin, the flurbiprofen has an anti-inflammatory effect, and the cisplatin and the flurbiprofen are simultaneously released at the same position in the cell in a prodrug connecting manner to reverse the drug resistance of tumor cells to the cisplatin, thereby synergistically killing tumors and enhancing an anti-tumor effect.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry and relates to a chemical prodrug and its preparation method and application. Background technique [0002] As a representative drug in the field of inorganic medicinal chemistry, cisplatin has been used in the clinical trials of various solid tumors such as ovarian cancer, testicular cancer, bladder cancer, and lung cancer since it was approved for use by the US Food and Drug Administration (FDA) in 1978. First-line chemotherapy is one of the most widely used broad-spectrum anticancer drugs in clinical practice. Its mechanism of action is: after cisplatin enters the cell and is activated, it binds to DNA in the nucleus to form an adduct, inhibits the transcription and replication of DNA, and induces apoptosis. Cisplatin is effective, but its disadvantages are also obvious, such as dose-limiting toxicity (ototoxicity, nephrotoxicity, neurotoxicity, bone marrow suppression, etc.), severe gastroi...

Claims

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Application Information

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IPC IPC(8): C07C51/00C07C57/58A61K33/24A61K31/192A61K47/55A61P35/00
CPCA61K31/192A61K33/24C07C51/00C07C51/60C07C57/58A61K2300/00
Inventor 梁兴杰李婵谭竞杰李书仪任磊
Owner THE NAT CENT FOR NANOSCI & TECH NCNST OF CHINA
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