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10-hydroxyamptothecin derivative, and its preparation method and application

A technology of hydroxycamptothecin and derivatives, applied in the field of medicine, can solve the problems of application limitation, poor solubility, large toxic and side effects, etc.

Inactive Publication Date: 2012-05-30
FUDAN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, its application is limited due to its poor solubility and high toxicity and side effects.

Method used

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  • 10-hydroxyamptothecin derivative, and its preparation method and application
  • 10-hydroxyamptothecin derivative, and its preparation method and application
  • 10-hydroxyamptothecin derivative, and its preparation method and application

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0021] Example 1. Synthesis of 9-formyl-10-acetoxycamptothecin

[0022]

[0023] Add 500mg (1.27mmol) of 9-formyl-10-hydroxycamptothecin and 100mL of anhydrous chloroform to a 250mL round bottom flask. After stirring, add 0.11mL (1.56mmol) of acetyl chloride and 0.36 of triethylamine. mL, heated and stirred at 50℃ to react, followed by TLC, and the reaction was complete after 1h. After the reaction solution cooled down, 100 mL of chloroform was added, washed successively with water, saturated sodium bicarbonate solution and saturated brine, dried over anhydrous sodium sulfate, filtered to remove sodium sulfate, and concentrated under reduced pressure to obtain a yellow crude product, which was subjected to silica gel column chromatography. Elute with methyl chloride / methanol (60 / 1) to obtain 445.6 mg of pale yellow powder, with a molecular weight of 434.40 and a yield of 80.5%.

Embodiment 2

[0024] Example 2. Synthesis of 9-formyl-10-benzyloxycamptothecin

[0025]

[0026] In a 250mL round bottom flask, add 500mg (1.27mmol) of 9-formyl-10-hydroxycamptothecin, 526.6mg of anhydrous potassium carbonate, and 100mL of acetone. After stirring, add 0.45mL (3.79mmol) of benzyl bromide and heat. The reaction was stirred at reflux, followed by TLC, and the reaction was complete after 8 hours. After the reaction solution is cooled, it is filtered and the filter cake is washed with acetone. After the combined mother liquor is evaporated to remove the solvent under reduced pressure, it is recrystallized with acetone to obtain 548.4 mg of light yellow powder with a molecular weight of 482.48 and a yield of 89.5%.

Embodiment 3

[0027] Example 3. Synthesis of 9-hydroxymethyl-10-acetoxycamptothecin

[0028]

[0029] Add 500mg (1.15mmol) of 9-formyl-10-acetoxycamptothecin in a 50mL round bottom flask, and 25mL of methanol. After stirring to dissolve, add 65mg (1.72mmol) of sodium borohydride. Stir at room temperature for reaction, followed by TLC After 30 minutes, the reaction is complete. After filtration, the filtrate was evaporated to remove the solvent to obtain a crude product, which was recrystallized from chloroform / methanol to obtain 537.3 mg of pale yellow powder with a molecular weight of 436.41 and a yield of 85.2%.

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PUM

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Abstract

The invention, belonging to the technical field of medicine, relates to a compound, that is, 10-hydroxyamptothecin derivative, and its preparation method and pharmaceutical application. The compound is represented as formula 1, wherein X=-H, -R, -COR, R represents alkyl with 1-8 carbon atoms, the alkyl represents alkane, alkylene or aryl; Y=-H, -R', -COR, R' represents alkyl with 1-8 carbon atoms, and the alkyl represents alkane, alkylene or aryl. The results of anti-tumor bioactivity in vitro selection tests show that the compound disclosed herein has significant inhibiting effect on the growth activity of tumor cells, and the compound can be further used for preparing anti-tumor active medicines for treating tumors.

Description

Technical field [0001] The present invention belongs to the field of medical technology, and relates to compound 10-hydroxycamptothecin derivatives and preparation methods and pharmaceutical uses thereof. The derivatives have significant inhibitory activity on tumor cell lines and have good application prospects in the field of tumor treatment. Background technique [0002] Camptothecin and Hydroxylcamptothecin are alkaloids extracted from camptotheca acuminata, a plant of the Davidia family unique to China. It selectively acts on DNA topoisomerase I (Top I). ), to prevent cancer cells from replicating and exert anti-cancer effects. However, its application is limited due to its poor solubility and large side effects. In the nearly 40 years since the first isolation, hundreds of new camptothecin derivatives and analogues have been synthesized all over the world, and a variety of camptothecins with good efficacy, small side effects and good solubility have been screened out. Cla...

Claims

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Application Information

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IPC IPC(8): C07D491/22A61K31/4745A61P35/00
Inventor 张倩李嘉俊董孟杰王国林
Owner FUDAN UNIV
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