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Cyclic lipopeptide derivative and preparation and application thereof

A kind of derivative and cyclolipopeptide technology, which is applied to cyclolipopeptide derivatives and their preparation, and the application field of the cyclolipopeptide derivatives in antibacterial, which can solve the problems of low activity of plant pathogens and the like

Active Publication Date: 2020-06-30
FUDAN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Its structure is obtained by spectral analysis (structure as formula I), it has broad spectrum, but the activity to phytopathogens is low as determined by antifungal bioassay

Method used

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  • Cyclic lipopeptide derivative and preparation and application thereof
  • Cyclic lipopeptide derivative and preparation and application thereof
  • Cyclic lipopeptide derivative and preparation and application thereof

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preparation example Construction

[0127]The preparation method of the cyclic lipopeptide derivatives of the present invention can be prepared by the commonly used amino acid condensation method in the field. It can also be prepared according to the preparation method of the present invention. The preparation method of the invention comprises the synthesis of the cyclic peptide skeleton and the alkylation of the cyclic peptide skeleton. The synthesis of the cyclic peptide skeleton includes the preparation of the peptide chain (or amino acid chain) and the preparation of the cyclic peptide skeleton.

[0128] The preparation of the peptide chain (or amino acid chain) comprises the following steps: using 2-chlorotrityl chloride resin (2-Cl-Trt resin) as a carrier, passing the Fmoc-L-Asn-OH reagent in the first step Load Fmoc-L-Asn on the resin, and then remove Fmoc by deprotection treatment to obtain resin NH loaded with L-Asn 2 -L-Asn-(2-Cl-Trt resin); then replace Fmoc-L-Asn-OH with different amino acid reagen...

Embodiment 1

[0143] Synthetic method of cyclolipopeptide derivatives

[0144] 1: Synthesis of Cyclic Peptide Skeleton

[0145] 1.1 Synthesis of amino acid chains:

[0146] The synthesis starts with loading of L-Asn onto 2-chlorotrityl chloride (2-Cl-Trt) resin.

[0147] (1) 2-Chlorotrityl chloride resin (2-Cl-Trt resin) (1.1mmol / g, 0.1mmol) was transferred to a reaction vessel, washed with anhydrous DCM (3×5mL), and Swell in water DCM (5 mL) for 30 minutes. Fmoc-L-Asn-OH (0.3mmol) and DMF (Fmoc-L-Asn-OH:DMF 1:1) and DIPEA (0.6mmol) dissolved in DCM were added, and the mixture was incubated under N 2 Stir under atmosphere for 3 hours. After the coupling (Fmoc-L-Asn-(2-Cl-Trt resin)) was completed, the resin (Fmoc-L-Asn-(2-Cl- Trt resin)), dried under vacuum, and weighed to check the completion of this resin loading.

[0148] (2) Swell the resin obtained in the above steps in DMF (3×5mL), and treat it with DMF (10mL) containing 20% ​​piperidine for 30 minutes. 5mL) to further wash the...

Embodiment 2

[0185] Activity Test of Cyclolipopeptide Derivatives

[0186]1. Activity detection method

[0187] 1.1 Bacteria experiment

[0188] All biological tests were performed with a modified broth microdilution test recommended by the Clinical and Laboratory Standards Institute (CLSI) that had been developed to determine in vitro antimicrobial activity with little modification.

[0189] All compounds were tested against different bacterial strains: Bacillus cereus, Bacillus subtilis, Staphylococcus epidermidis, Pseudomonas putida, Klebsiella pneumoniae ( Klebsiella pneumonia), Escherichia coli (E. coli).

[0190] Bacterial strains were grown overnight at 37°C in LB medium and bacterial growth was measured by turbidity as optical density at λ = 600 nm (OD600). Dilute the bacterial strain to 10 per ml 6 working solution of colony forming units. Compounds were dissolved in DMSO to form stock solutions. 96-well round-bottom polypropylene plates and 100 μl of diluted bacterial strai...

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Abstract

The invention relates to a cyclic lipopeptide derivative and preparation and application thereof. The cyclic lipopeptide derivative is a compound with a structure as shown in a formula A, wherein A1,A2, A3, A4, A5, A6, A7 and A8 are all amino acids, and every two of the A1, A2, A3, A4, A5, A6, A7 and A8 are connected through an amido bond. The A1 is L-Asn; the A2 is L-Tyr or D-Tyr; the A3 is L-Asn or D-Asn; the A4 is L-Ser or D-Ser; the A5 is L-Asn or D-Asn; the A6 is L-Gln; the A7 is L-Pro; and the A8 is L-Cys, and a hydrogen atom on -SH of L-Cys is substituted by one of the following groups: a C1-C18 alkyl group, C4-C11 carboxylic acid, a C4-C11 alkyl cyano group, and a C4-C11 carboxylic acid methyl ester. The cyclic lipopeptide derivative has an excellent antibacterial effect.

Description

technical field [0001] The invention belongs to the technical field of biomedicine, and specifically relates to a cyclolipopeptide derivative, its preparation and the antibacterial application of the cyclolipopeptide derivative. Background technique [0002] Fungal infection is a growing medical problem that imposes an enormous economic burden on healthcare worldwide, costing treatment in the billions each year. Medically important fungal infections can be broadly divided into two categories: The first category is fungi that infect surface structures such as the skin, skin structures or mucous membranes. The second category is invasive fungal infections, which involve sterile body parts such as the blood, central nervous system, or organs, including the lungs, liver, and kidneys. Many fungi that cause invasive disease infect most humans, but the vast majority of clinically important disease they cause occurs in immunocompromised populations. [0003] Treatment options for ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K7/64C07K1/04C07K1/06A61K38/08A61P31/04A61P31/10
CPCA61K38/00A61P31/04A61P31/10C07K7/64Y02P20/55
Inventor 张琪拉杰·曼达拉普王方婷
Owner FUDAN UNIV
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