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Polymyxin derivatives and their preparation methods and applications

A technology for polymyxin and derivatives, which is applied in the fields of polymyxin derivatives and their preparation and application, can solve the problems of complex natural components of polymyxin, unstable clinical efficacy, uncertain structure and the like

Active Publication Date: 2021-07-23
MEDICINE & BIOENG INST OF CHINESE ACAD OF MEDICAL SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] Regarding the research on the biological function of a single component of polymyxin antibiotics, the proportion of the main components of polymyxins currently used in clinical practice varies among different brands, and even the proportion of the main components in different batches of the same brand There is also a gap in the ratio, resulting in instability of clinical efficacy (He J, Ledesma K R, Lam W Y, et al.Variability of polymyxin B major components in commercial formulations.Int J AntimicrobAgents.2010,35(3):308-310.He H , Li J C, Nation R L, et al.Pharmacokinetics offour different brands of colistimethate and formed colistin in rats.JAntimicrob Chemother.2013,68(10):2311-2317.)
The natural components of polymyxin are complex. Tam et al. separated natural polymyxin B by preparative liquid chromatography to obtain polymyxin B1, B2, B3, B4 and B1-Ile and tested the in vitro antibacterial activity of a single component for the first time (Tam V H, Cao H, Ledesma K R, et al.In vitro potency of variouspolymyxin B components.Antimicrob Agents Chemother.2011,55(9):4490-4491.), except for the main components B1 and B2 in clinical medicine , E1, E2 have antimicrobial activity and nephrotoxic research reports (Roberts KD, Azad M A, Wang J, et al. Antimicrobial Activity and Toxicity of the Major Lipopeptide Components of Polymyxin B and Col istin: Last-Line Antibiotics against Multidrug-Resistant Gram-Negative Bacteria.ACS Infect.Dis.2015,1(11):568-575.), the research on other components is mostly limited to the report of material discovery, and some even the structure is not very sure, lack of various components Systematic study of biological functions of fractions

Method used

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  • Polymyxin derivatives and their preparation methods and applications
  • Polymyxin derivatives and their preparation methods and applications
  • Polymyxin derivatives and their preparation methods and applications

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0604] Example 1: Preparation of 6-Methoxyhexanoyl-Dab-Thr-Dab-Cycle(4-10)[Dab-Dab-D-Phe-Leu-Dab-Dab-Thr] (Compound 1)

[0605] The sequence of adding the protected amino acid and side chain carboxylic acid into the synthesis route is: Fmoc-Dab-OAllyl, Fmoc-Dab(Dde)-OH, Fmoc-Dab(Boc)-OH, Fmoc-Thr(tBu)-OH, Fmoc-Dab(Boc)-OH, 6-methoxyhexanoic acid, Fmoc-Thr(tBu)-OH, Fmoc-Dab(Boc)-OH, Fmoc-Dab(Boc)-OH, Fmoc-Leu-OH, Fmoc-D-Phe-OH

[0606] The sequence of adding the protected amino acid and side chain carboxylic acid into the synthetic route 2 is: Fmoc-Dab-OAllyl, Fmoc-Leu-OH, Fmoc-D-Phe-OH, Fmoc-Dab(Boc)-OH, Fmoc-Dab (Dde)-OH, Fmoc-Dab(Boc)-OH, Fmoc-Thr(tBu)-OH, Fmoc-Dab(Boc)-OH, 6-methoxyhexanoic acid, Fmoc-Thr(tBu)-OH, Fmoc-Dab(Boc)-OH

[0607] Synthetic Route 3 The sequence of adding the protected amino acid and side chain carboxylic acid to the reaction is: Fmoc-Dab-OAllyl, Fmoc-Dab(Boc)-OH, Fmoc-Leu-OH, Fmoc-D-Phe-OH, Fmoc-Dab (Boc)-OH, Fmoc-Dab(Dde)-OH, Fmoc-Dab(Boc)-OH,...

Embodiment 2

[0611] Example 2: Preparation of N,N-dimethylaminovaleryl-Dab-Thr-Dab-ring (4-10) [Dab-Dab-D-Phe-Leu-Dab-Dab-Thr] (Compound 2)

[0612] The sequence of adding the protected amino acid and side chain carboxylic acid into the synthesis route is: Fmoc-Dab-OAllyl, Fmoc-Dab(Dde)-OH, Fmoc-Dab(Boc)-OH, Fmoc-Thr(tBu)-OH, Fmoc-Dab(Boc)-OH, N,N-Dimethylaminovaleric acid, Fmoc-Thr(tBu)-OH, Fmoc-Dab(Boc)-OH, Fmoc-Dab(Boc)-OH, Fmoc-Leu- OH, Fmoc-D-Phe-OH

[0613] The sequence of adding the protected amino acid and side chain carboxylic acid into the synthetic route 2 is: Fmoc-Dab-OAllyl, Fmoc-Leu-OH, Fmoc-D-Phe-OH, Fmoc-Dab(Boc)-OH, Fmoc-Dab (Dde)-OH, Fmoc-Dab(Boc)-OH, Fmoc-Thr(tBu)-OH, Fmoc-Dab(Boc)-OH, N,N-dimethylaminovaleric acid, Fmoc-Thr(tBu)- OH, Fmoc-Dab(Boc)-OH

[0614] Synthetic Route 3 The sequence of adding the protected amino acid and side chain carboxylic acid to the reaction is: Fmoc-Dab-OAllyl, Fmoc-Dab(Boc)-OH, Fmoc-Leu-OH, Fmoc-D-Phe-OH, Fmoc-Dab (Boc)-OH, Fmoc-Dab(Dd...

Embodiment 3

[0618] Example 3: Preparation of 3-Oxooctanoyl-Dab-Thr-Dab-Ring (4-10) [Dab-Dab-D-Phe-Leu-Dab-Dab-Thr] (Compound 5)

[0619]The sequence of adding the protected amino acid and side chain carboxylic acid into the synthesis route is: Fmoc-Dab-OAllyl, Fmoc-Dab(Dde)-OH, Fmoc-Dab(Boc)-OH, Fmoc-Thr(tBu)-OH, Fmoc-Dab(Boc)-OH, 3-oxooctanoic acid, Fmoc-Thr(tBu)-OH, Fmoc-Dab(Boc)-OH, Fmoc-Dab(Boc)-OH, Fmoc-Leu-OH, Fmoc- D-Phe-OH

[0620] The sequence of adding the protected amino acid and side chain carboxylic acid into the synthetic route 2 is: Fmoc-Dab-OAllyl, Fmoc-Leu-OH, Fmoc-D-Phe-OH, Fmoc-Dab(Boc)-OH, Fmoc-Dab (Dde)-OH, Fmoc-Dab(Boc)-OH, Fmoc-Thr(tBu)-OH, Fmoc-Dab(Boc)-OH, 3-oxooctanoic acid, Fmoc-Thr(tBu)-OH, Fmoc- Dab(Boc)-OH

[0621] Synthetic Route 3 The sequence of adding the protected amino acid and side chain carboxylic acid to the reaction is: Fmoc-Dab-OAllyl, Fmoc-Dab(Boc)-OH, Fmoc-Leu-OH, Fmoc-D-Phe-OH, Fmoc-Dab (Boc)-OH, Fmoc-Dab(Dde)-OH, Fmoc-Dab(Boc)-OH, Fmoc-Thr(...

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Abstract

Provided are polymyxin derivatives with a general formula I structure, their preparation methods and applications. The preparation method of described polymyxin derivative comprises the following steps: (1) free amino group of protected basic amino acid Fmoc-AA-OP side chain and halogenated resin react to obtain Fmoc-AA-OP-resin; (2) Fmoc-AA-OP-resin is coupled one by one to obtain linear polypeptide-resin; (3) linear polypeptide-resin is selectively deprotected and solid-phase cyclized to obtain cyclic polypeptide-resin; (4) cyclic polypeptide-resin is obtained by Acid hydrolysis and ether precipitation to obtain a crude cyclic polypeptide; (5) the crude product is purified and / or salted, and freeze-dried to obtain a pure cyclic polypeptide. The polymyxin derivatives can be used for the preparation of antibacterial drugs, especially for the preparation of antibacterial drugs with expanded antibacterial spectrum, improved antibacterial activity, and reduced nephrotoxicity, including the preparation of antibacterial drugs against "super bacteria" carrying NDM‑1 genes drug.

Description

technical field [0001] The present invention relates to polymyxin derivatives and a preparation method thereof, and also relates to the use of the inventive compound in the preparation of antibacterial drugs, especially the use in the preparation of antibacterial drugs with expanded antibacterial spectrum, improved antibacterial activity, and reduced nephrotoxicity, including the preparation of The use of antibacterial drugs against "super bacteria" carrying NDM-1 gene, as well as the pharmaceutical composition containing this type of compound as an active component and its application belong to the field of biomedicine. Background technique [0002] Polymyxin, discovered in 1947, is a general term for a series of cationic antibacterial polypeptides produced by Bacillus polymyxa, with different types of structures such as A, B, C, D, E, F, K, M, P, S and T , the molecular weight is around 1200D. The common structural feature of polymyxin antibiotics is that it consists of t...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07K7/62A61K38/12A61P31/04
CPCY02P20/55A61P31/04C07K7/62A61K38/00A61K38/12C07K1/061C07K1/12C07K1/30
Inventor 崔阿龙李卓荣金洁高岩胡辛欣游雪甫陈阳何琪杨
Owner MEDICINE & BIOENG INST OF CHINESE ACAD OF MEDICAL SCI