Selenium polymer prodrug micelle with reduction responsiveness, preparation method and application

A polymer, responsive technology that can be used in the field of biomedicine to solve problems such as limiting mass production applications, synthesis process complexity, and non-reproducibility.

Active Publication Date: 2020-10-20
NANKAI UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the increasingly cumbersome structure design in the current similar research also brings the complexity and non-reproducibility of the synthesis process, which limi

Method used

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  • Selenium polymer prodrug micelle with reduction responsiveness, preparation method and application
  • Selenium polymer prodrug micelle with reduction responsiveness, preparation method and application
  • Selenium polymer prodrug micelle with reduction responsiveness, preparation method and application

Examples

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preparation example Construction

[0056] The preparation method of the above-mentioned reduction-responsive selenium polymer prodrug micelles comprises the following steps:

[0057] S1, under a protective gas atmosphere, using ethyl 7-bromoheptanoate and sodium perselenide as raw materials to synthesize the compound of formula (Ⅲ);

[0058] S2, the compound of formula (Ⅲ) is deesterified under alkaline conditions to generate the compound of formula (Ⅳ);

[0059] S3. Under a protective gas atmosphere, dissolve the compound of formula (IV), 3-aminobenzyl alcohol, HOAT, and HATU in a solvent, add N,N-diisopropylethylamine (DIEA) at 0°C, and generate the formula ( V) compounds;

[0060] S4, reacting the compound of formula (V) and carbonyldiimidazole to prepare the compound of formula (VI);

[0061] S5, under protective gas atmosphere, formula (Ⅵ) compound and amino polyethylene glycol monomethyl ether (mPEG 2000 -NH 2 ,M w =2.0KDa) reaction, replace and prepare the selenium polymer of formula (I); self-assem...

Embodiment 1

[0066] A method for preparing a reduction-responsive selenium polymer prodrug micelle, comprising the following steps:

[0067] 1) Preparation of 7,7'-diselenideethyl heptanoate from ethyl 7-bromoheptanoate;

[0068] The compound 7-bromoheptanoic acid ethyl ester (2.42g, 13.87mmol) was added into the reaction flask, tetrahydrofuran (15mL) was added under nitrogen protection, and sodium perselenide (6.94mmol) was added at the same time; reacted at 40°C for 8h, returned to room temperature, and spun Dry tetrahydrofuran, extract the aqueous phase with ethyl acetate (30mL×3) three times, combine the organic phases and dry with anhydrous sodium sulfate, filter with suction, and spin to dry the solvent to obtain 1.68g of light yellow oil, yield: 74%; figure 1 The obtained 7,7'-diselenide ethyl heptanoate NMR pattern is given 1 H NMR;

[0069] 2) preparing 7,7'-diselenideptanoic acid from ethyl 7,7'-diselenideptanoate;

[0070] Compound 7,7'-diselenide ethyl heptanoate (4.00g, 8.8...

Embodiment 2

[0078] A method for preparing a reduction-responsive selenium polymer prodrug micelle, comprising the following steps:

[0079]1) Preparation of ethyl 7,7'-diselenidediheptanoate from ethyl 7-bromoheptanoate, the steps are the same as in Example 1, the difference is that the reaction at 25°C for 12h, ethyl 7-bromoheptanoate and perselenium The molar ratio of sodium chloride is 3:1;

[0080] 2) Preparation of 7,7'-diselenide heptanoate from ethyl 7,7'-diselenide diheptanoate, the steps are the same as in Example 1, the difference is that the reaction time is 2h, 7,7'-diselenide diheptanoate The mol ratio of ethyl diheptanoate and sodium hydroxide is 1:2;

[0081] 3) Prepare DmSeSAHA from 7,7'-diselenideheptanoic acid, the steps are the same as in Example 1, the difference is that the reaction temperature is 25°C, 7,7'-diselenideheptanoic acid: 3-aminobenzyl alcohol: The molar ratio of HATU:HOAT:DIEA is 1:4:4:4:4;

[0082] 4) Prepare CDI-DmSeSAHA from DmSeSAHA, the steps are ...

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Abstract

The invention discloses a selenium polymer prodrug micelle with reduction responsiveness, a preparation method and application, and belongs to the technical field of biological medicine. The micelle is prepared by applying the following selenium prodrug polymer; the selenium prodrug polymer has a structure as shown in a formula (I); according to the invention, by using vorinostat as a model, firstly, a vorinostat derivative containing a di-selenium bond is synthesized, then hydrophilic fragments polyethylene glycol are connected to both ends of the derivative, and then the obtained product isprepared into the nano micelle, so that a drug is stable in a body, and a histone deacetylase inhibiting effect is obviously improved; and the preparation method is simple, convenient, green and environmental-friendly, and has the potential of mass production.

Description

technical field [0001] The invention belongs to the technical field of biomedicine, and in particular relates to a reduction-responsive selenium polymer prodrug micelle, a preparation method and an application. Background technique [0002] Cancer treatment has shifted from traditional chemotherapeutics to more mechanized targeted therapies, and disturbances in the balance of histone acetyltransferases (HATs) and deacetylases (HDACs) can cause abnormalities in cell morphology, cycle, and differentiation, leading to cancer progression. Occurrence; among them, HDAC plays an important role in the above relationship, so it becomes the target of cancer targeted therapy. [0003] At present, HDAC inhibitors have effects on a variety of tumors in preclinical experiments, but their current clinical indications are still limited to the treatment of hematological tumors. Although many clinical studies on solid tumors are underway, there is no In conclusion, in the clinical trials con...

Claims

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Application Information

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IPC IPC(8): A61K47/69A61K47/60A61K31/167A61K41/00A61P35/00C08G65/337
CPCA61K47/6907A61K47/60A61K41/0038A61K31/167A61P35/00C08G65/337
Inventor 王燕铭沈杰孟丽王达远王雅洁
Owner NANKAI UNIV
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