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Preparation method of polyamidoamine dendritic macromolecular structure modifier and application thereof

A polyamidoamine-type, macromolecular structure technology, applied in the direction of antibacterial drugs, can solve the problems of cytotoxicity, in-depth research and application, and achieve the effect of low synthesis cost, good water solubility, and inhibition of expression

Inactive Publication Date: 2014-02-05
FOURTH MILITARY MEDICAL UNIVERSITY
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] Thanks to PAMAM-NH 2 The cytotoxicity greatly limits its further in-depth research and application

Method used

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  • Preparation method of polyamidoamine dendritic macromolecular structure modifier and application thereof
  • Preparation method of polyamidoamine dendritic macromolecular structure modifier and application thereof
  • Preparation method of polyamidoamine dendritic macromolecular structure modifier and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0032] Embodiment 1: Synthesis of LED209 carboxyl derivatives

[0033] The following are the synthesis routes of two carboxyl derivatives of LED209, which are para-position (para-) and meta-position (meta-) carboxyl groups. The synthesis routes are as follows:

[0034] .

[0035] (1) Synthesis of Compound 1: Take a 100 mL round bottom flask, add dichloromethane (DCM, 50 mL), and while stirring, add aniline (SM-2, 5.1 g, 54.8 mmol), triethylamine (11 g , 109 mmol) and p-acetamidobenzenesulfonyl chloride (SM-1, 11.68 g, 50 mmol), stirred at room temperature for 10 h. The next day, dilute the reaction solution with 100 mL DCM, add 30 mL of 1 N HCl solution to wash the organic phase 3 times, wash with Na 2 SO 4 After thorough drying and spin-drying, 12 g of the target compound was obtained with a yield of 82.7%. The theoretical molecular weight of compound 1 is 290.5, and the detection value M-1 peak is 289.45 (see Figure 8 ).

[0036] (2) Synthesis of compound 2: 1 N...

Embodiment 2

[0045] Embodiment 2: the synthesis of para / meta-PAMAM G3.0-LED209

[0046] Accurately weigh para-LED209-COOH (30 mg, 0.070 mmol) prepared in Example 1, G3.0 PAMAM-NH 2 (242 mg, 0.035 mmol) was dissolved in N,N-dimethylformamide (DMF, 10 mL), triethylamine (21 mg, 0.21 mmol) and 1-hydroxybenzotriazole (HOBT, 9.5 mg , 0.070 mmol), and the reaction solution was stirred overnight at room temperature. The reaction solution was purified by preparative chromatography (pre-HPLC) to obtain 55 mg of light yellow oil.

[0047] Accurately weigh the meta-LED209-COOH (30 mg, 0.070 mmol) prepared in Example 1, G3.0 PAMAM-NH 2 (242 mg, 0.035 mmol) was dissolved in N,N-dimethylformamide (DMF, 10 mL), triethylamine (21 mg, 0.21 mmol) and 1-hydroxybenzotriazole (HOBT, 9.5 mg , 0.070 mmol), and the reaction solution was stirred overnight at room temperature. The reaction solution was purified by preparative chromatography (pre-HPLC) to obtain 56 mg of a pale yellow oil. NMR was determined ...

Embodiment 3

[0053] Example 3: In vitro antibacterial activity and cytotoxicity investigation of G3.0 PAMAM-LED209

[0054] 1. Materials and instruments

[0055] 1.1 Experimental strains

[0056] The 12 strains of Gram-negative bacteria, including 9 standard strains and 3 drug-resistant strains (see Table 2), were used in this part of the experiment.

[0057] 9 strains of standard strains and 3 strains of drug-resistant strains used in the test of table 2

[0058] Chinese name English name English abbreviations Standard strain Type strain TS Escherichia coli Escherichia coli ATCC 25922 E. coli Escherichia coli Escherichia coli K12MG1655 E. coli MG 1655 Pseudomonas aeruginosa 261H Pseudomonas aeruginosa ATCC 27853 P. aeruginosa Klebsiella pneumoniae Klebsiella pneumonia ATCC13883 K. pneumonia Salmonella Enteritidis 262H Salmonella enterica ATCC 9150 S. enteric Acinetobacter baumannii Ac...

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Abstract

The invention discloses a preparation method of a polyamidoamine dendritic macromolecular structure modifier and a pharmacy application. The modifier is obtained by covalent coupling of polyamidoamine dendritic macromolecules and a LED209 carboxyl derivative through an amide bond. By the adoption of the polyamidoamine dendritic macromolecular structure modifier, cytotoxicity of PAMAM-NH2 is obviously reduced, and affinity with pathogenic bacteria can be raised. In the meantime, through inhibiting a QseC acceptor, expression of a key disease-associated gene of a pathogen is inhibited, thus establishing the foundation for the realization of the targeting antibacterial effect of the modifier.

Description

technical field [0001] The invention relates to a polymer compound, in particular to a polyamidoamine-type dendritic macromolecular structure modification, a preparation method and a pharmaceutical application of the modification. Background technique [0002] At present, due to the spread of various bacterial drug resistance caused by the abuse of antibiotics intensified around the world, many infectious diseases that could have been cured are becoming incurable diseases. Infection by drug-resistant bacteria leads to increased mortality and complications of infection. Diseases caused by drug-resistant bacteria infection have become a common disaster for all mankind. At present, bacterial drug resistance has shown a tendency to develop into multidrug resistance, and some bacteria have evolved into "super bacteria" that are difficult to control. An article in the "Lancet" magazine in August 2010 introduced a superbug "New Delhi metallo-β-lactamase 1", referred to as NDM-1, w...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C08G83/00A61K31/795A61P31/04
Inventor 罗晓星薛小燕白卉陈晓晴达飞孟静茹
Owner FOURTH MILITARY MEDICAL UNIVERSITY
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