Application of artesunate and podophyllotoxin conjugates in anti-leukemia drugs and preparation method

A technology of podophyllotoxin and artesunate, which can be used in drug combination, antineoplastic drugs, organic chemistry, etc., and can solve the problems of high toxicity and side effects

Inactive Publication Date: 2015-09-23
ZUNYI MEDICAL UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003] In addition, podophyllotoxin is an important lignin natural product, its main pharmacological activities include anti-tumor and anti-virus, etc.

Method used

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  • Application of artesunate and podophyllotoxin conjugates in anti-leukemia drugs and preparation method
  • Application of artesunate and podophyllotoxin conjugates in anti-leukemia drugs and preparation method
  • Application of artesunate and podophyllotoxin conjugates in anti-leukemia drugs and preparation method

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0015] Example 1: Preparation of artesunate-podophyllotoxin conjugates (1)

[0016] Add artesunate (0.25mmol), podophyllotoxin (0.25mmol) and 4-dimethylaminopyridine (0.3mmol) into a 10mL pear-shaped bottle, then add N,N-dimethylformamide (4mL) to dissolve , add 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.5mmol) under ice-water bath cooling, stir and react at 25°C for 6 hours, pour the reaction solution into water, stir and filter with suction , washed with water, and dried in vacuum, the obtained crude product was subjected to column chromatography (the eluent was a mixed solution of ethyl acetate and petroleum ether at a volume ratio of 1:2) to obtain the coupled artesunate and podophyllotoxin shown in formula (I). material with a yield of 60%.

[0017] MP: 139-141°C; IR (KBr) 3622, 2938, 1779, 1588, 11485, 1456, 1420, 1376, 1331, 1240, 1127, 1037, 927 cm -1 ; 1 H NMR (400 MHz, CDCl 3 ) δ 6.80 (s, 1H), 6.52 (s, 1H), 6.39 (s, 2H), 5.98 (dd, J = 5.5, 1.3 H...

Embodiment 2

[0018] Example 2: Preparation of artesunate-podophyllotoxin conjugates (2)

[0019] Add artesunate (0.25mmol), podophyllotoxin (0.5mmol) and 4-dimethylaminopyridine (0.3mmol) into a 10mL pear-shaped bottle, then add dichloromethane (4mL) to dissolve, and add it under cooling in an ice-water bath 1-Ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.5mmol), stirred and reacted at 30°C for 4 hours, poured the reaction liquid into water, stirred, filtered with suction, washed with water, and dried in vacuum. The resulting crude product was subjected to column chromatography (the eluent was a mixture of ethyl acetate and petroleum ether at a volume ratio of 1:2) to obtain the conjugate of artesunate and podophyllotoxin represented by formula (I), with a yield of 50 %.

Embodiment 3

[0020] Example 3: Proliferation inhibitory activity of conjugates represented by formula (I) on human leukemia cells

[0021] CCK-8 staining method:

[0022] Cells were seeded in 96-well plates in CO 2 After culturing in the incubator for 24 hours, add drug-containing medium with a concentration gradient, set up a negative control group, a positive control group and a vehicle group at the same time, take out the culture plate after continuing to cultivate for 72 hours, add 10 microliters of CCK-8 solution, and cultivate for 3 After 1 hour, select 450nm on the microplate reader to measure the absorbance value (OD value), and calculate the inhibition rate of each group, and the inhibition rate (%) = [(OD value of the negative control group-OD value of the experimental group) / OD of the negative control group Value] × 100%. Using SPSS17.0 software to calculate the half inhibitory concentration (IC 50 ).

[0023] In this experiment, according to the CCK-8 method, artesunate and...

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Abstract

The invention discloses application of artesunate and podophyllotoxin conjugates in anti-leukemia drugs according to formula (I) and a preparation method. The preparation method includes using artesunate and podophyllotoxin as raw materials and esterifying to obtain artesunate and podophyllotoxin conjugates according to formula (I). The invention further discloses application of artesunate and podophyllotoxin in anti-leukemia drugs. The conjugates have anti-leukemia cell activity and can be used for preparing anti-leukemia drugs. The artesunate and podophyllotoxin has different degrees of anti-proliferation actions to leukemia K562 cell and leukemia Adriamycin persister K562/Adr.

Description

technical field [0001] The invention relates to a conjugate of artesunate and podophyllotoxin, a preparation method thereof, and an application in the preparation of anti-leukemia drugs. Background technique [0002] Artemisinin is a sesquiterpene lactone natural product isolated from Artemisia annua of Compositae with peroxy bridge bonds, and it is currently used as the main antimalarial drug worldwide (Chem. Soc . Rev. 2010, 39, 435.). In addition, studies have also found that artemisinin has other activities, such as anti-tumor and anti-virus (Bioorg. Med. Chem. Lett. 2001, 11, 5; Bioorg. Med. Chem. 2013, 21, 3702). At the same time, in order to improve the properties of artemisinin solubility and other aspects, a variety of artemisinin derivatives were synthesized by researchers, among which artesunate, as a typical representative drug, is mainly used to treat Plasmodium falciparum (Antimicrob . Agents Chemother. 2010, 54, 3730.). Moreover, human trials have confirmed...

Claims

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Application Information

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IPC IPC(8): C07D519/00A61K31/365A61P35/02
CPCC07D519/00A61K31/365
Inventor 张磊王京
Owner ZUNYI MEDICAL UNIVERSITY
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