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A kind of thioene ether compound and its synthesis method and application in polypeptide cyclization

A technology of sulfenyl ethers and compounds, applied in the field of biochemistry, can solve problems such as complex synthesis of cyclic peptides, and achieve good biocompatibility, green raw materials, and easy operation

Active Publication Date: 2020-07-31
XIAMEN UNIV
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] The purpose of the present invention is to solve the complex technical problem of cyclic peptide synthesis in the prior art, to provide a thioene ether compound and its synthesis method and its application in polypeptide cyclization

Method used

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  • A kind of thioene ether compound and its synthesis method and application in polypeptide cyclization
  • A kind of thioene ether compound and its synthesis method and application in polypeptide cyclization
  • A kind of thioene ether compound and its synthesis method and application in polypeptide cyclization

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0050] The synthesis of the thioene ether compound comprises the following steps:

[0051] Step 1, the synthesis of compound methyl 4-(2,2-dicyano-1-hydroxyvinyl)benzoate

[0052]

[0053] Specific steps are as follows:

[0054] (1) Put sodium hydride (1.8 g, 75.0 mmol) in a round bottom flask, add anhydrous tetrahydrofuran (30 mL) to disperse, and stir vigorously in an ice bath at 0 °C under nitrogen atmosphere protection. Malononitrile (2.5 g, 37.5 mmol) was dissolved in anhydrous tetrahydrofuran (30 mL), and slowly added dropwise to the above system. The reaction system was kept in an ice bath at 0° C., and stirred for 1 h in the ice bath after the dropwise addition.

[0055] (2) Methyl 4-chloroformylbenzoate (7.5 g, 37.5 mmol) was dissolved in anhydrous tetrahydrofuran (30 mL). While maintaining an ice bath at 0°C, the solution was slowly added dropwise to the system. After the dropwise addition, the reaction system was transferred to room temperature, allowed to wa...

Embodiment 2

[0097] Cyclization of Peptides

[0098]

[0099]The cyclization reaction molecule mother solution (500 μmol / L, 20 μL), peptide mother solution (500 μmol / L, 10 μL), N-acetyl-L-cysteine ​​(5 mmol / L, 4 μL) and TCEP (5 mmol / L, 4 μL) Add to phosphate buffer (pH=7.4, 200mmol / L, 50μL), and add water (12μL). The concentration of each component in the final system is: thioene ether (100 μmol / L), polypeptide (50 μmol / L), TCEP (200 μmol / L), N-acetyl-L-cysteine ​​(200 μmol / L) and phosphate buffer solution (pH=7.4, 100mmol / L). The system was placed at room temperature for 90 min. The reaction was monitored using high performance liquid chromatography. After the reaction, the reaction product was characterized by ultraviolet-visible absorption spectrum and mass spectrometry. Quantification according to high performance liquid chromatography, as shown in Table 1 is the characterization data of the cyclization reaction, and the conversion rate of the polypeptide is 100%.

[0100] Tabl...

Embodiment 3

[0104] Selectivity test for peptide cyclization

[0105]

[0106] The cyclization reaction molecular mother solution (500μmol / L, 20μL), polypeptide H-CGGGKGW-NH 2 Mother solution (500μmol / L, 10μL), N-acetyl-L-cysteine ​​(5mmol / L, 4μL) and TCEP (5mmol / L, 4μL) were added to phosphate buffer (pH=7.4, 200mmol / L, 50μL ), and supplemented with water (12 μL). The concentration of each component in the final system is: thioene ether (100 μmol / L), polypeptide (50 μmol / L), TCEP (200 μmol / L), N-acetyl-L-cysteine ​​(200 μmol / L) and phosphate buffer solution (pH=7.4, 100mmol / L). The system was placed at room temperature for 90 min. The reaction was monitored using high performance liquid chromatography. After the reaction, the reaction product was characterized by ultraviolet-visible absorption spectrum and mass spectrometry. According to the characterization results, the cysteine ​​at the N-terminal of the polypeptide reacted with the cyclized molecule, and 100% conversion of the ...

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Abstract

The invention relates to a thioalkene ether compound, a synthesis method thereof and application thereof in polypeptide cyclization, belongs to the technical field of biochemistry. The thioalkene ether compound can be used for quickly cyclizing a polypeptide containing one nitrogen-terminal cysteine and one intrachain cysteine under mild conditions, thereby constructing cyclic peptides. The methodis adopted in posttranslational modification, a phage display library for displaying the cyclized polypeptides can be constructed, and the cyclic peptides which can be applied to detection, treatmentand the like can be further constructed on the basis of the phage display library.

Description

technical field [0001] The invention relates to the technical field of biochemistry, in particular to a thioene ether compound, its synthesis method and its application in polypeptide cyclization. Background technique [0002] In recent years, peptides have been widely used in the fields of chemistry, life science and medicine. Peptide is a molecule between biological macromolecules and organic small molecules, which has the advantages of both. Peptide molecules have the characteristics of high diversity, high affinity and high selectivity of biological macromolecules. Compared with traditional biomacromolecules, it has the characteristics of easy synthesis, derivation and modification of small organic molecules (see European journal of medicinal chemistry 2015, 94, 459, Bioorganic & medicinal chemistry 2018, 26, 2759). [0003] General polypeptides, especially linear peptides, are relatively flexible and have multiple conformations due to the lack of interactions between ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C319/20C07C323/59C07K1/113
CPCC07B2200/07C07C323/59C07K1/113
Inventor 吴川六李卓儒郑晓莉
Owner XIAMEN UNIV
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