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A class of reduction-responsive amphiphilic small molecule prodrugs and preparation methods thereof

An amphiphilic, small molecule technology, used in pharmaceutical formulations, organic active ingredients, medical preparations containing active ingredients, etc. To improve the synergistic effect of dual drugs, achieve accurate diagnosis and treatment, and improve the effect of drug loading

Inactive Publication Date: 2019-01-22
SOUTHWEST UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In some research reports, hydrophilic polyethylene glycol is introduced into the CPT molecule through the connection of ester bond or amide bond. Very stable, so small-molecule prodrugs based on ester bonds or amide bonds cannot achieve selective release of drugs at tumor sites, and it is difficult to effectively reduce the toxic and side effects caused during drug delivery

Method used

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  • A class of reduction-responsive amphiphilic small molecule prodrugs and preparation methods thereof
  • A class of reduction-responsive amphiphilic small molecule prodrugs and preparation methods thereof
  • A class of reduction-responsive amphiphilic small molecule prodrugs and preparation methods thereof

Examples

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preparation example Construction

[0029] The invention provides a method for preparing a reductively responsive amphiphilic small molecule prodrug, characterized in that: the method for preparing a reductively responsive amphiphilic small molecule prodrug comprises the following steps:

[0030] (1) Preparation of reductively responsive camptothecin (CPT) precursor: camptothecin (CPT), triphosgene, 4-dimethylaminopyridine (DMAP), bis(2-hydroxyethyl) disulfide ( BHD) mixture was dispersed into dichloromethane (DCM), stirred overnight, and purified to obtain the desired product camptothecin (CPT) precursor;

[0031] (2) Preparation of amphiphilic small-molecule prodrugs: the camptothecin (CPT) precursor containing disulfide bonds is dispersed in the corresponding organic solvent, and the hydrophilic drug molecule folic acid (FA) or methotrexate (MTX) is introduced. Reduction-responsive amphiphilic small-molecule prodrugs FA-CPT and MTX-CPT were obtained through ylation or amidation reactions, and the desired prod...

Embodiment 1

[0037] According to attached figure 1 In the shown reaction formula, under the condition of argon (Ar) atmosphere, a certain amount of pure camptothecin (CPT) molecule is firstly dissolved in anhydrous dichloromethane (DCM), and then 4-dimethylaminopyridine is added respectively (DMAP) and solid triphosgene in DCM were stirred for 20 minutes in the dark, then a certain amount of bis(2-hydroxyethyl) disulfide (BHD) in anhydrous tetrahydrofuran (THF) was added and stirred overnight. After separation and purification, the single hydroxyl substituted camptothecin precursor (BHD-CPT) is obtained; under the conditions of temperature ≤ 0°C and argon (Ar) atmosphere, a certain amount of single hydroxyl substituted camptothecin precursor (BHD-CPT) -CPT), hydrophilic drug molecule folic acid (FA) (substituent R=H), 4-dimethylaminopyridine (DMAP) dissolved in anhydrous N,N-dimethylformamide (DMF), 0 Stir in the dark for 30 minutes at ℃, then add a certain amount of 1-(3-dimethylaminopr...

Embodiment 2

[0040] The small-molecule prodrug prepared in Example 1 was prepared into nanomicelles: at room temperature, 5 mg / mL of dimethyl sulfoxide (DMSO) equipped with the reducing-response amphiphilic small-molecule prodrug product FA-CPT The solution was slowly added dropwise into deionized water, stirred for a certain period of time, and dialyzed to obtain light yellow small molecule prodrug nanomicelles ( image 3 shown in the upper right corner), characterized by dynamic light scattering (DLS) and transmission electron microscopy (TEM). Such as image 3 Shown is the DLS diagram of small molecule prodrug nanomicelles. The results show that the average diameter of small molecule prodrug nanomicelles is 46.4nm, and its particle size distribution coefficient is 0.218, showing a good monodisperse state. Such as Figure 4 Shown is the transmission electron microscope image of the small molecule prodrug nanomicelle, indicating that the result shows that the diameter of the micelle i...

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Abstract

The invention relates to the field of chemical drugs, in particular to preparation and application of a reducibility responding amphiphilic micromolecular prodrug. The preparation comprises the following steps that a reducibility responding camptothecin (CPT) precursor is prepared, and the reducibility responding amphiphilic micromolecular prodrug is prepared. A self-assembly delivery system for the prodrug effectively improves the drug uploading capacity and the bi-drug synergistic effect and solves the problems that according to an existing micromolecular prodrug technology, the carrier proportion is high, the drug uploading capacity is low, and it is hard to guarantee the selectivity controllable releasing of drugs.

Description

technical field [0001] The invention relates to the field of chemical medicines, in particular to the preparation and application of a reduction-responsive amphiphilic small-molecule prodrug biostimuli-responsive type amphiphilic small-molecule prodrug. Background technique [0002] Camptothecin (CPT for short, chemical structural formula: C20H16N2O4, CAS number: 7689-03-4, relative molecular weight: 348.43) is a kind of hydrophobic compound purified from camptothecin widely distributed in central and southwestern my country. Anti-cancer drugs. Camptothecin has strong anticancer activity against liver cancer and head and neck cancer. The possible mechanism of action is that active camptothecin can stabilize the covalent compound of topoisomerase Ⅰ and DNA, forming a class of ternary dissociable complex, leading to cell death by causing DNA loss. [0003] Due to the small molecular size of camptothecin and its extremely low solubility in water, problems such as non-specific ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D519/00A61K31/519A61P35/00
CPCC07D519/00
Inventor 许志刚康跃军薛鹏石潇潇侯美丽高永娥
Owner SOUTHWEST UNIV
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