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Method for drug release by cleavage of ester bond

A technology of drugs and ester bonds, applied in the field of drug release, can solve the problems of slow sulfhydryl exchange process and changing drug function, etc.

Inactive Publication Date: 2017-03-15
CHANGZHOU UNIV +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Although this sulfhydryl exchange reaction is widely used in intracellular drug release, the thiol exchange process is also slow (the half-life of the reaction is usually as long as more than ten hours), and the introduction of sulfhydryl groups on small molecule drugs often changes the drug properties. Function

Method used

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  • Method for drug release by cleavage of ester bond
  • Method for drug release by cleavage of ester bond
  • Method for drug release by cleavage of ester bond

Examples

Experimental program
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Effect test

Embodiment 1

[0029] Such as figure 1 As shown, the drug small molecule Preparation: (1) D-ribose (80g, 532.9mmol) was dissolved in acetone 1000ml, and H was added dropwise at room temperature 2 SO 4 (2.4ml) and stirred at room temperature for 2.5 hours, the mixture was washed with solid NaHCO 3 Neutralized, filtered and concentrated by evaporation under reduced pressure to give a colorless syrup (1a), yield 74%.

[0030] (2) Compound 1a (20.36g, 107.1mmol) was dissolved in anhydrous THF (800ml), and vinylmagnesium bromide (480.0ml, 480.0mmol, 1.0M THF solution) was added dropwise at -78°C, and the reaction mixture was Stirring at 0°C for 3 hours afforded the compound (2a), the content of compound 2a (main product) in the product (2a+2b) is 74%.

[0031] (3) Compound 2a (19.25g, 88.2mmol) was used in CH 2 Cl 2 (330ml) solution, sodium periodate (204.0ml, 132.4mmol, 0.65M aqueous solution) solution was added dropwise at 0°C, and the reaction mixture was stirred at room temperature...

Embodiment 2

[0042] Change the short peptide sequence TPSPFSH to RGD, and the rest of the steps are the same as in Example 1. The addition reaction of glutathione and RGD polypeptide-small molecules leads to the cleavage of ester bonds for drug release.

Embodiment 3

[0044] The drug small molecule 1b was changed to doxorubicin, and the rest of the steps were the same as in Example 1. The addition reaction of glutathione and TPSPFSH polypeptide-doxorubicin results in the breakage of the ester bond for drug release.

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Abstract

The invention provides a method for releasing medicines by virtue of ester bond rupture. The method comprises the following steps: coupling small medicine molecules containing unsaturated carbanyl groups with tumor targeting polypeptide by virtue of ester bonds to obtain a polypeptide-small molecule compound, and then performing addition reaction on glutathione in cells and the polypeptide-small molecule compound to ensure that the ester bonds are broken, and the purpose of releasing the medicines can be achieved. According to the method for releasing the medicines by virtue of ester bond rupture, the small molecules containing the unsaturated carbanyl groups are coupled with fluorescence-labelled polypeptide molecules by virtue of the ester bonds to obtain a short peptide-small molecule compound. Inventors discover that the addition reaction can be performed between glutathione and the unsaturated carbanyl groups in the short peptide-small molecule compound to cause ester bond rupture so as to ensure that the medicines are released; and moreover, the ester bond rupture rate has a linear relationship with the concentration of glutathione, and when the polypeptide-small molecule compound enters the cells, the small molecules can be rapidly released, and the high sensitivity of the reaction on the concentration of glutathione is very suitable for selective release in the cells.

Description

technical field [0001] The invention belongs to the technical field of drug release, and relates to a novel ester bond breaking reaction and its application, in particular to an intracellular glutathione-induced ester bond breaking in a polypeptide-small molecule complex, which is used for intracellular selective release . Background technique [0002] With the improvement of people's living standards, the acceleration of the pace of life in modern society, the change of lifestyle, environmental pollution and many other factors, cancer has become the main killer of human health. In recent years, although great progress has been made in the diagnosis and treatment of tumors, the morbidity and mortality of common malignant tumors are still high. The targeted diagnosis and treatment of tumors has become one of the most important research directions in the field of tumor diagnosis and treatment. At present, the commonly used targeting molecules mainly use the ligands or antibod...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): A61K47/64A61K31/357A61P35/00
Inventor 王建浩李进晨蒋鹏举邱琳李静燕王车礼秦玉琴滕一万柳丽周翔
Owner CHANGZHOU UNIV
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