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Water-soluble tryptanthrin polymer derivative modified by polyethylene glycol, preparation method and application thereof

A technology of polyethylene glycol and tryptanthrin, which is applied in the field of water-soluble tryptanthrin polymer derivatives and its preparation, can solve problems such as improving the water solubility of tryptanthrin, and achieve improved bioavailability, water solubility, The effect of broad application prospects

Active Publication Date: 2017-11-24
FOURTH MILITARY MEDICAL UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] At present, there is no report on improving the water solubility of tryptanthrin by chemical methods

Method used

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  • Water-soluble tryptanthrin polymer derivative modified by polyethylene glycol, preparation method and application thereof
  • Water-soluble tryptanthrin polymer derivative modified by polyethylene glycol, preparation method and application thereof
  • Water-soluble tryptanthrin polymer derivative modified by polyethylene glycol, preparation method and application thereof

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0049] The synthetic route is attached figure 1 , 0.248g tryptanthrin was dissolved in 20mL tetrahydrofuran, 0.328g hydroxyethylhydrazine was dissolved in 2mL ethanol solution, vacuumed for 20min, protected by nitrogen, and stirred at room temperature for 12h. After the reaction, purify by column chromatography to collect the target product—TRYP-NNHCH 2 CH 2 Oh. The qualitative characterization of the fracture of its hydrazone bond is shown in the attached image 3 , wherein, (a) is pH7.4, t=15min; (b) is pH5.0, t=3min; (c) is pH5.0, t=30min.

[0050] 41.5mg mPEG 2000 -COOH, 12mgDCC and 6mgDMAP were dissolved in an appropriate amount of anhydrous dichloromethane, and reacted in an ice-water bath for 24h. Add appropriate amount of intermediate to mPEG 2000 -COOH solution, add 2 mL of pyridine at the same time, and continue to keep the ice-water bath for 24 hours. After the reaction, remove the solvent under reduced pressure, add saturated sodium bicarbonate solution, filt...

Embodiment 2

[0053] Dissolve 0.248g tryptanthrin in 15mL tetrahydrofuran, add 1.5mL hydrazine hydrate, 50°C oil bath, react for 10h, and purify by column chromatography to obtain the target product—TRYP-NNH 2 . 63.4mg of MPEG-COOH, 18.3mg of DDC, and 20.6mg of NHS were dissolved in anhydrous dichloromethane, and reacted in an ice bath for 24 hours to obtain the activated product of mPEG-COOH. The activated product of the intermediate and mPEG-COOH was dissolved in anhydrous dichloromethane and reacted at room temperature for 24h. Rotary evaporation, saturated NaHCO 3 The solution was washed three times, extracted with ethyl acetate, and the product—TRYP-NNHCO-PEG was collected.

Embodiment 3

[0055] Weigh 100mg of mPEG-OH and 13.1mg of carbonyldiimidazole (CDI) into a 25mL eggplant-shaped bottle, add 5mL of anhydrous dichloromethane, and stir at room temperature for 24 hours. After the reaction is complete, evaporate the solvent under reduced pressure, and add excess With anhydrous ether, the white precipitate was collected and dried in vacuo to obtain 36.7 mg of mPEG-CDI. The product was dissolved in 5 mL of dichloromethane with hydrazine hydrate and triethylamine. The post-experiment processing is the same as the above step to obtain mPEG-NHNH 2 . This reacts with an equivalent of tryptanthrin to give TRYP-NNH-mPEG.

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Abstract

The invention discloses a polyethylene-glycol-modification water-solubility tryptanthrin polymer derivative, a preparing method thereof and an application thereof, and belongs to the technical field of drug preparing. The polyethylene-glycol-modification water-solubility tryptanthrin polymer derivative is prepared after tryptanthrin and modified polyethylene glycol are reacted or prepared after modified tryptanthrin and polyethylene glycol are reacted. By means of the prepared water-solubility tryptanthrin polymer derivative (a water-solubility tryptanthrin prodrug), the solubility of the tryptanthrin can be increased by 200-3,000 times; the content of the tryptanthrin in the prodrug is 1%-90%, the acid sensitivity (acid sensitivity hydrazone bond rupturing) characteristic is achieved, the tryptanthrin can be dissociated in the weak acid environment at the tumor portion and the inflammation portion, and therefore drug activity is developed; nano-micelle can be prepared from the tryptanthrin polymer derivative with a mixed solvent dialysis method, and nano-micelle can be formed after the tryptanthrin and PEG are dissolved into water in a certain proportion.

Description

technical field [0001] The invention belongs to the technical field of medicine preparation, and in particular relates to a polyethylene glycol-modified water-soluble tryptanthrin polymer derivative and a preparation method and application thereof. Background technique [0002] The natural product Tryptanthrin (TRYP) is derived from indigo and other plants of the genus Equus, and it is reported that it has strong toxicity to breast cancer MCF-7, lung cancer NCI-H460, and central nervous system cancer SF-268 cell lines. Liver cells have a protective effect, can improve allergic dermatitis, and effectively treat diseases such as intestinal disorders and inflammation. That is, tryptanthrin and some of its derivatives have pharmacological activities such as antibacterial, anti-inflammatory, anti-tumor, and anti-oxidative. [0003] Although tryptanthrin has strong pharmacological effects and great medicinal value, its poor solubility in water limits its absorption in the body, r...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C08G65/333A61K47/60A61P29/00A61P35/00
CPCC08G65/33396
Inventor 吴红张倩杨铁虹范黎王四旺
Owner FOURTH MILITARY MEDICAL UNIVERSITY
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