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Camptothecin and artesunate conjugate, preparation method and application thereof

A technology of artesunate and conjugates, which is applied in the field of preparation of antitumor drugs, can solve the problems of poor solubility and high toxicity, and achieve the effect of reducing damage

Active Publication Date: 2014-11-26
ZHEJIANG UNIV OF TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, camptothecin has not been used clinically because of its high toxicity and poor solubility

Method used

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  • Camptothecin and artesunate conjugate, preparation method and application thereof
  • Camptothecin and artesunate conjugate, preparation method and application thereof
  • Camptothecin and artesunate conjugate, preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0027] Example 1: Preparation of camptothecin and artesunate conjugates (1)

[0028] Add artesunate (15mmol) and dichloromethane (10mL) into a 25mL round bottom flask, stir to dissolve at 25°C, then add EDCI (15mmol), stir at 25°C for 0.5h, then add DMAP (50mg), stir at 25°C After 0.5h, camptothecin (5mmol) was finally added, stirred and reacted at 25°C for 3h to obtain a light yellow suspension. Sodium aqueous solution and saturated sodium bicarbonate aqueous solution were washed, then dried with anhydrous magnesium sulfate, suction filtered, the filtrate was concentrated to dryness under reduced pressure, and the obtained concentrate was subjected to silica gel column chromatography, and the eluent was dichloromethane with a volume ratio of 100:1 Mix the liquid with methanol, collect the eluate containing the target component, concentrate and dry to obtain the conjugate of camptothecin and artesunate represented by formula (I), with a yield of 80%.

[0029] MP:194.8-195.3℃ ...

Embodiment 2

[0030] Example 2: Preparation of camptothecin and artesunate conjugates (2)

[0031] Add artesunate (10mmol) and chloroform (20mL) into a 25mL round bottom flask, stir to dissolve at 30°C, then add EDCI (10mmol), stir at 30°C for 0.5h, then add DMAP (50mg), stir at 25°C for 0.5h , finally add camptothecin (3mmol), stir and react at 30°C for 3h to obtain a light yellow suspension, after the reaction, add dichloromethane (40mL) to the reaction solution, filter with suction, and the filtrate is successively washed with saturated aqueous sodium chloride solution and saturated aqueous sodium bicarbonate solution, then dried with anhydrous magnesium sulfate, suction filtered, and the filtrate was concentrated to dryness under reduced pressure, and the obtained concentrate was subjected to silica gel column chromatography, and the eluent was dichloromethane and methanol at a volume ratio of 100:1 For the mixed solution, the eluate containing the target component was collected, concen...

Embodiment 3

[0032] Embodiment 3: The compound shown in formula (I) has inhibitory activity on tumor cell proliferation

[0033] 1) Test material

[0034] Liver cancer cells (SMMC-7721) and human breast cancer cells (MCF-7) were purchased from the Cell Bank of the Type Culture Collection Committee of the Chinese Academy of Sciences.

[0035] Standard products of camptothecin and artesunate were purchased from Bailingwei Biotechnology Co., Ltd.

[0036] The cell maintenance medium is 2% serum concentration medium, RPMI1640 medium is used for SMMC-7721, and DMEM medium is used for MCF-7.

[0037] The camptothecin and artesunate conjugate prepared in Example 1, camptothecin, artesunate, dimethyl sulfoxide (DMSO) were diluted with cell maintenance solution respectively, and 6 concentration gradients were made for each sample : 0.032, 0.16, 0.8, 4, 20, 100 μmol / L, 4 replicate wells for each concentration gradient.

[0038] 2) Detection method

[0039] Human liver cancer cells (SMMC-7721) an...

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Abstract

The present invention discloses a camptothecin and artesunate conjugate represented by a formula (I). The preparation method comprises the steps of dissolving camptothecin represented by a formula (II) and artesunate represented by a formula (III) in an organic solvent, carrying out a stirring reaction at a temperature of 15-50 DEG C under the effects of 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride and 4-dimethylaminopyridine, performing TLC tracking monitoring until the reaction is over, and post-treating the reaction solution to obtain the camptothecin and artesunate conjugate represented by the formula (I). The camptothecin and artesunate conjugate of the present invention can be used for preparing various anti-tumor drugs. The formulas (I), (II) and (III) are shown as follows.

Description

(1) Technical field [0001] The invention relates to a camptothecin-artesunate conjugate, a preparation method thereof, and an application in the preparation of antitumor drugs. (2) Background technology [0002] Camptothecin is derived from the Chinese plant Camptothecin. Due to its unique mechanism of action, a large number of camptothecin derivatives have been synthesized and studied in the field of anticancer drug research. Camptothecin and its derivatives have good inhibitory effects on various cancer cells, such as: lung cancer, prostate cancer, breast cancer, colon cancer, gastric cancer, ovarian cancer, melanoma, lymphoma, etc. However, camptothecin has not been used clinically because of its high toxicity and poor solubility. Another kind of artemisinin extracted from Artemisia annua of Compositae has been used as an antimalarial drug for more than 2,000 years, and artemisinin and its derivatives have always been considered safe and effective. Studies have found th...

Claims

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Application Information

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IPC IPC(8): C07D519/00A61K31/4745A61P35/00A61P35/02
CPCC07D519/00
Inventor 李庆勇王文超
Owner ZHEJIANG UNIV OF TECH
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