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Combretastatin compound and preparation method and application thereof

A combretastatin and compound technology, applied in the field of combretastatin compounds and their preparation, can solve the problems of poor water solubility, toxic and side effects, etc., and achieve the effects of reducing toxicity, strong inhibitory activity, and good inhibitory and killing effects

Inactive Publication Date: 2011-11-23
LANZHOU UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, butatins have poor water solubility and have certain toxic and side effects

Method used

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  • Combretastatin compound and preparation method and application thereof
  • Combretastatin compound and preparation method and application thereof
  • Combretastatin compound and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0018] 3-N-[(-formyl-2′,2′,6′,6′-tetramethylpiperidine-4′-nitroxyl amido)-L-glycine]-combretastatin amide (Ia )Synthesis

[0019] Synthesis of raw material N-(1-oxyl-2,2,6,6-tetramethyl-oxygen-carbonyl)-L-amino acid: 2,2,6,6-tetramethyl-4-hydroxypiperidine Dissolve in 20mL of water and 20mL of methanol, then add 0.30g of sodium tungstate and 0.20g of EDTA, put it on a magnetic stirrer, start to stir, after dissolving, add 30% hydrogen peroxide in batches, and continue stirring for 10 hours to get orange red Solid 2,2,6,6-tetramethyl-4-hydroxypiperidine nitroxide free radical. Add 2,2,6,6-tetramethyl-4-hydroxypiperidine nitroxide dissolved in dry ether dropwise into stirred N,N-carbonyldiimidazole dissolved in dry tetrahydrofuran, and stir at room temperature for 3 hours , forming N-(1-oxyl-2,2,6,6-tetramethyl-oxygen-carbonyl)-imidazole, the generated N-(1-oxyl-2,2,6,6-tetra Methyl-oxy-carbonyl)-imidazole was added to a solution of p-toluenesulfonic acid monohydrate in dry a...

Embodiment 2

[0028] 3-N-[(-formyl-2′,2′,6′,6′-tetramethylpiperidine-4′-nitroxyl amido)-L-alanine]-combretastatin amide Synthesis of (Ib)

[0029]The experimental procedure is the same as in Example 1, only alanine is used instead of glycine. The detection data of the product obtained from the reaction are as follows: yield: 68%; m.p.75-77°C; , 1239, 1126, 1028; ESR: An=16.16G, g 0 = 2.006; MS m / z 585 [M+H] + ;HRMS: m / zcalcd for C 31 h 42 N 3 o 8 : 607.2864[M+Na] + , Found: 607.2855[M+Na] + .

Embodiment 3

[0031] 3-N-[(-formyl-2′,2′,6′,6′-tetramethylpiperidine-4′-nitroxyl amido)-L-phenylalanine]-combretastatin Synthesis of Amide (Ic)

[0032] The experimental procedure is the same as that of Example 1, except that glycine is replaced by phenylalanine. The detection data of the product obtained from the reaction are as follows: yield: 70%; m.p.78-80°C; , 1239, 1125, 1029; ESR: An=15.98G, g 0 = 2.006; MS m / z 661 [M+H] + ;HRMS: m / z calcd for C 37 h 46 N 3 o 8 : 683.3177[M+Na] + , Found: 683.3166[M+Na] + .

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Abstract

The invention discloses a combretastatin compound and a preparation method. The preparation method of the combretastatin compound of the invention comprises the following steps: dissolving 3'-amino combretastatin and N-(1-oxyl-2,2,6,6,-tetramethyl-oxygen-carbonyl)-L-amino acid in dried dichloromethane, uniformly stirring under argon protection, adding dicyclohexylcarbodiimide and 1-hydroxybenzotriazole, stirring and reacting under argon protection, filtering and removing white precipitates after the reaction, removing the solvent by distillation to obtain a crude product, purifying the crude product by column chromatography, and eluting the product by petroleum ether and ethyl acetate liquid with a volume ratio of 10:1-5:1 to obtain the target product. The combretastatin compound of the invention is applicable to the preparation of anticancer medicaments, and is especially applicable to the preparation of medicaments for treating leukemia, liver cancer, gastric cancer, and cervical cancer.

Description

technical field [0001] The present invention relates to an organic compound that can be used as medicine, as well as the preparation method and application of the compound, specifically, the present invention relates to combretastatin compounds and the preparation method and application thereof. Background technique [0002] Combretastatin (combretastatin) is a natural cis-stilbene compound with anti-tumor activity isolated from the trunk of Combretum caffrum in South Africa. Cancer, lung cancer, bladder cancer, leukemia and many other tumor cells have a good inhibitory effect, including some multi-drug resistant cancer cells, and have a good selective effect on the proliferation and spread of vascular endothelial cells. Therefore, it has become a highly concerned active lead molecule in the development of anti-tumor drugs (Alessandra Cirla, et al. Nat. Prod. Rep., 2003, 20, 558-564). In recent years, the research on combretastatin at home and abroad has mainly focused on a...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D211/94C07D401/12A61K31/45A61K31/454A61P35/00A61P35/02
Inventor 刘映前杨柳李晓静李林海寇亮
Owner LANZHOU UNIVERSITY
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