Applications of compound containing N-oxidized tertiary amine group as cell mitochondria targeting carrier

A technology for oxidizing tertiary amine groups and tertiary amines, applied in the field of medicine, can solve problems such as toxic and side effects, and achieve the effects of reducing toxic and side effects, good water solubility and biocompatibility, and reducing enrichment

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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, such molecules are positively charged and highly hydrophobic. After being used as targeting groups to modify drug molecules or polymer carriers, they are easy to bind to immune proteins, so they will be quickly cleared after intravenous injection and cannot Once they reach the lesion site, there is no way to talk about further targeted delivery of cell mitochondria; at the same time, these molecules themselves have relatively large toxic and side effects

Method used

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  • Applications of compound containing N-oxidized tertiary amine group as cell mitochondria targeting carrier
  • Applications of compound containing N-oxidized tertiary amine group as cell mitochondria targeting carrier
  • Applications of compound containing N-oxidized tertiary amine group as cell mitochondria targeting carrier

Examples

Experimental program
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Embodiment 1

[0062] Embodiment 1: ODEAEMA-Cy5.5 fluorescent probe synthesis

[0063] The present application is based on the application of N-oxidized tertiary amine molecules as mitochondrial fluorescent probes, one embodiment of which is N-oxidized-methacrylic acid 2-(N,N-diethylamino)ethyl ester (ODEAEMA) Molecule-linked fluorescent molecules serve as mitochondrial fluorescent probes. More specifically, in one embodiment, the linked fluorescent molecule is Cy5.5, which is synthesized as follows:

[0064]

[0065] The synthesis method is as follows:

[0066] 2-(N,N-Diethylamino)ethyl methacrylate (DEAEMA, 9.25 g) was dissolved in 20 mL of chloroform. The reaction system was placed in an ice-water bath, and a mixed solution of 11.17 g m-chloroperoxybenzoic acid and 100 mL chloroform was slowly added dropwise to the system. After the reaction system was stirred at room temperature for 12 hours, 17 g of potassium carbonate was slowly added. After stirring for 10 minutes, the reaction...

Embodiment 2

[0069] Example 2: PODEAEMA Targets Mitochondrial Carrier Synthesis

[0070] An embodiment of the application of the N-oxidized tertiary amine-based polymer as a mitochondria-targeting carrier includes linking fluorescent molecules to prepare a mitochondrial fluorescent probe-type polymer. More specifically, in one embodiment, the loaded fluorescent molecule is Cy5.5, which is synthesized as follows:

[0071]

[0072] Wherein the mole fraction x is 0.8-0.95, n=3-300.

[0073] The synthesis method is as follows:

[0074] (1) Synthesis of PODEAEMA-NHS.

[0075] 2-(N,N-diethylamino)ethyl methacrylate (DEAEMA, 5.37g) and tert-butyl methacrylate (tBMA, 0.37g), 0.0041g of ethyl 2-isobromobutyrate, After putting 0.085 g of 2,2'-bipyridine, 0.038 g of cuprous bromide and 2 mL of methanol into the polymerization bottle, nitrogen gas was continuously fed for 30 minutes to remove oxygen. Then seal and react at 30°C for 6 hours. After the reaction was finished, the catalyst was rem...

Embodiment 3

[0084] Embodiment 3: Preparation of PODEAEMA-b-polySN38 block copolymer

[0085] The application of the N-oxidized tertiary amine polymer as a drug carrier in the present application, one embodiment is to use the N-oxidized tertiary amine polymer as a hydrophilic chain, which is connected to the drug molecule or its polymer to form Amphiphilic, bonded drugs form nanoparticles or micelles by their assembly in aqueous solution. More specifically, in one embodiment, the loaded drug is 7-ethyl-10-hydroxycamptothecin (SN38), which is synthesized as follows:

[0086]

[0087] Wherein, m=1-200, n=1-300.

[0088] The synthesis method is as follows:

[0089] After putting DMAEMA (240mg), ethyl 2-isobromobutyrate (3.9mg), pentamethyldiethylenetriamine (40mg), cuprous bromide (10mg), and DMF1mL into the polymerization bottle, nitrogen gas was continuously introduced Oxygen was removed for 30 minutes. Then seal and react at 40°C for 4 hours. Under the protection of argon, directly i...

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Abstract

The invention discloses applications of a compound containing an N-oxidized tertiary amine group as a cell mitochondria targeting carrier, wherein the compound contains one or a plurality of N-oxidized tertiary amine structure units, the N-oxidized tertiary amine structure unit at least comprises one selected from the following groups represented by formulas (I), (II) and (III), R1 and R2 are respectively and independently alkyl, substituted alkyl, aryl, substituted aryl or a polymer main chain, and R3 and R4 are respectively and independently hydrogen, alkyl, substituted alkyl, aryl, substituted aryl or a polymer main chain. According to the present invention, the compounds are electrically neutral, have the similar water solubility, the similar biocompatibility and the similar long bloodcirculation time to polyvinyl alcohol (PEG), and can rapidly enter cells and be highly-selectively enriched in cell mitochondria; and the drug modified with the compound containing the N-oxidized tertiary amine group or the probe can specifically treat or label mitochondria.

Description

technical field [0001] The invention relates to the technical field of medicine, in particular to the application of a compound containing an N-oxidized tertiary amine group as a cell mitochondria targeting carrier. Background technique [0002] Mitochondria are important organelles in human tissue cells and participate in a variety of metabolic processes. Their dysfunction is closely related to cancer, neurodegenerative diseases, obesity and ischemia-reperfusion injury and other refractory diseases [Pan Lingli et al., Medical Review 2015, 21( 1) 37-38]. The key to efficient treatment of mitochondrial diseases is to enable drug molecules to efficiently target mitochondria. However, the small molecular properties and hydrophobicity of drug molecules cause them to be rapidly degraded or cleared in the body, and the efficiency of reaching the lesion site and entering the mitochondria after entering the cell is very low. [0003] Using molecules or macromolecules that specific...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K47/32A61K49/00
CPCA61K47/32A61K49/0052A61K49/0054
Inventor 申有青钟寅
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