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Polymyxin derivative and preparation method thereof

A technology of polymyxin and derivatives, applied in the field of polymyxin derivatives and its preparation, can solve the problems of nephrotoxicity and neurotoxicity, limited application, lack of treatment methods, etc., and achieve reduced physiological toxicity and high antibacterial activity , Improve the effect of antibacterial activity

Inactive Publication Date: 2010-10-06
梁浩 +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Polymyxin B has potential nephrotoxicity and neurotoxicity, which once limited its clinical application
However, due to the lack of effective treatment for multidrug-resistant (MDR) Gram-negative bacilli in clinical practice, people have begun to pay attention to the clinical use of polymyxin B in recent years.

Method used

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  • Polymyxin derivative and preparation method thereof
  • Polymyxin derivative and preparation method thereof
  • Polymyxin derivative and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0050] Embodiment 1: Carry out enzymatic hydrolysis to polymyxin B, the steps are as follows:

[0051] (1) Dissolve 35 grams of polymyxin B sulfate in 3 liters of 0.07M phosphate buffer (pH 7.0);

[0052] (2) Dissolve 6,000 U of ficin in 0.5 liter of 0.07M phosphate buffer (pH 7.0), and mix it with the above polymyxin B sulfate solution;

[0053] (3) Add 1 gram of dithiothreitol;

[0054] (4) After gentle mixing at 37°C for 24 hours, heat under reflux for a short time to inactivate the enzyme;

[0055] (5) After cooling, filter to remove the denatured enzyme, and adjust the pH to 2.0 with 6M HCl;

[0056] (6) Extract four times with 0.25 liter of n-butanol, and adjust the pH of the aqueous phase to 8.5 with 6M NaOH;

[0057] (7) Extract with n-butanol again, and adjust the pH of the aqueous phase to 5.1 with 6M HCl;

[0058] (8) The aqueous phase was concentrated under reduced pressure to 0.2 liters, and desalted using a Sephadex G-10 desalting column;

[0059] (9) After ...

Embodiment 2

[0061] Embodiment 2: to the chemical modification of enzymolysis product, the steps are as follows:

[0062] (1) The polymyxin B product after the above enzymatic hydrolysis was prepared into a 0.05M solution with water: dioxane: triethylamine (1:1:1, v / v), and 5M 2- (tert-butoxycarbonyloxyimino)-2-phenylacetonitrile;

[0063] (2) Incubate at 23°C for 20 minutes, add excess methanolic ammonia solution to terminate the reaction;

[0064] (3) Concentrate the reaction solution by rotary evaporation to dryness, redissolve with methanol, and filter;

[0065] (4) excessive diethyl ether is added in the filtrate, and the precipitation is collected by filtration;

[0066] (5) Purify the precipitate using flash silica gel column chromatography, the mobile phase is triethylamine:methanol:dichloromethane (1:13:86, v / v);

[0067] (6) Collect the main elution peak, and obtain the intermediate compound after freeze-drying;

[0068] (7) The intermediate compound is mixed with excess fluo...

Embodiment 3

[0072] Embodiment 3: to the chemical modification of enzymolysis product, step (1) to step (6) are the same as embodiment 2, and step (7) is as follows:

[0073] (7) The intermediate compound is mixed with excess fluorenylmethoxycarbonyl (Fmoc)-3,4-diaminophenylacetic acid-pentafluorophenyl ester, and condensed in the presence of dimethylformamide;

[0074] Step (8) to step (10) are the same as embodiment 2.

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Abstract

The invention discloses a polymyxin derivative and a preparation method thereof. Since zymohydrolysis, fatty acid chain on the end N of polymyxin B and one diaminobutyric acid residue are removed, a 3, 4-oxamido-benzoyl group is introduced through a chemical decoration technology or a benzene ring group with two fatty acid chains is introduced, so the polymyxin derivative is obtained. The derivative can be used for the clinical treatment of infection of Gram-negative multidrug resistance bacteria.

Description

technical field [0001] The invention relates to a polymyxin derivative and a preparation method thereof. Background technique [0002] Polymyxins are a class of basic linear cyclic cationic polypeptide antibiotics produced by Paenibacillus polymyxa, which contain a hydrophilic cyclic peptide head and a hydrophobic fatty acid tail. According to structural differences, it can be divided into components such as polymyxin A, B, C, D and E, and the molecular weight is about 1200D. Polymyxins (polymyxins) A-E have similar antibacterial spectrum and have strong bactericidal effect on a variety of Gram-negative bacteria. Studies have shown that polymyxins can destroy the permeability of the outer membrane and plasma membrane of Gram-negative bacteria, resulting in the leakage of intracellular substances and thus play a bactericidal effect. In addition, polymyxins B (polymyxinsB, PMB) not only has a bactericidal effect on a variety of Gram-negative bacteria, but also has an obvious...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K7/02C12P21/06C07K1/107A61P31/04
CPCY02P20/55
Inventor 梁浩滕峰
Owner 梁浩
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