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Resin, preparation method thereof and application of resin to preparation of head-to-tail cyclopeptides

A resin, head-to-tail technology, applied in the application field of preparation of head-to-tail cyclic peptides, can solve the problems of cumbersome operation and long cycle, and achieve the effect of optimizing chemical structure, optimizing chain length, chemical structure and connecting arm length

Active Publication Date: 2021-04-02
ANHUI UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The solid-phase chemical modification and liquid-phase recyclization of polypeptides often have the disadvantages of cumbersome operations and long cycles.

Method used

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  • Resin, preparation method thereof and application of resin to preparation of head-to-tail cyclopeptides
  • Resin, preparation method thereof and application of resin to preparation of head-to-tail cyclopeptides
  • Resin, preparation method thereof and application of resin to preparation of head-to-tail cyclopeptides

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0060] Example 1: Treat 2-chlorotrityl chloride resin with 1,2-ethanedithiol / 1,4-dibromomethylbenzene / 2-aminoethanethiol to obtain a new type of resin and apply it to the preparation of sulfur Ether bonded macrocyclic peptide cyclo-1.

[0061] In this embodiment, the resin and its preparation method and the specific synthesis process of using it to prepare the head-to-tail cyclic peptide include the following steps:

[0062] (1) Acid treatment of 2-chlorotrityl chloride resin (loading capacity: 0.56mmol / g, 80μmol): add 3mL of DCM containing 30% TFA to 143mg of resin, react at room temperature for 5 minutes, remove waste liquid.

[0063] (2) 1,2-ethanedithiol treatment: Dissolve 1,2-ethanedithiol (10eq, 76μL) in 3mL of DCM, transfer to acid-treated resin, react at room temperature for 10 minutes, repeat the process , until the resin faded to light yellow, DCM washed the resin 4 times.

[0064] (3) MeOH blocking: Add 3 mL of methanol blocking reagent (MeOH / DIEA / DCM, 0.4 mL / 0....

Embodiment 2

[0077] Example 2: Treat 2-chlorotrityl chloride resin with 1,6-hexanedithiol / 1,4-dibromomethylbenzene / 2-aminoethanethiol to obtain a new type of resin and apply it to the preparation of sulfur Ether bonded macrocyclic peptide cyclo-2.

[0078] The specific synthesis process of the resin and its preparation method and its use to prepare the head-to-tail cyclic peptide in this embodiment includes the following steps:

[0079] (1) Acid treatment of 2-chlorotrityl chloride resin (loading capacity: 0.56mmol / g, 80μmol): add 3mL of DCM containing 30% TFA to 143mg of resin, react at room temperature for 5 minutes, remove waste liquid.

[0080] (2) 1,6-hexanedithiol treatment: Dissolve 1,6-hexanedithiol (10eq, 121μL) in 3mL of DCM, transfer to acid-treated resin, react at room temperature for 10 minutes, repeat the process , until the resin faded to light yellow, DCM washed the resin 4 times.

[0081] (3) MeOH blocking: Add 3 mL of methanol blocking reagent (MeOH / DIEA / DCM, 0.4 mL / 0....

Embodiment 3

[0094]Example 3: Treat 2-chlorotrityl chloride resin with 1,8-octanedithiol / 1,4-dibromomethylbenzene / 2-aminoethanethiol to obtain a new type of resin and apply it to the preparation of sulfur Ether bonded macrocyclic peptide cyclo-3.

[0095] The specific synthesis process of the resin and its preparation method and its use to prepare the head-to-tail cyclic peptide in this embodiment includes the following steps:

[0096] (1) Acid treatment of 2-chlorotrityl chloride resin (loading capacity: 0.56mmol / g, 80μmol): add 3mL of DCM containing 30% TFA to 143mg of resin, react at room temperature for 5 minutes, remove waste liquid.

[0097] (2) 1,8-octanedithiol treatment: Dissolve 1,8-octanedithiol (10eq, 143μL) in 3mL of DCM, transfer to acid-treated resin, react at room temperature for 10 minutes, repeat the process , until the resin faded to light yellow, DCM washed the resin 4 times.

[0098] (3) MeOH blocking: Add 3 mL of methanol blocking reagent (MeOH / DIEA / DCM, 0.4 mL / 0.2...

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Abstract

The invention discloses resin, a preparation method thereof and application of the resin to preparation of head-to-tail cyclopeptides. The structural general formula of the resin is as shown in the specification. The new resin is obtained through sequential chemical modification (namely dithiol reagent modification, bis(bromomethyl)benzene modification and mercaptoethylamine modification) of 2-chlorotrityl chloride resin. Through Fmoc solid-phase synthesis and reaction of liquid-phase N-terminal bromoacetyl and C-terminal thiol, the resin can be directly used for preparing thioether bond-bonded head-to-tail cyclopeptides with different chain lengths and structures.

Description

technical field [0001] The invention relates to a resin, its preparation method and its application in the preparation of head and tail cyclic peptides. The resin provided by the invention can be used to rapidly prepare thioether-bonded head-to-tail cyclic peptides with different chain lengths and structures, which is beneficial to the structural optimization of the thioether linking arms of the head-to-tail thioether-bonded cyclic peptides. Background technique [0002] Head-to-tail macrocyclic peptides are structurally rigid, resistant to hydrolysis by various proteases, and possess higher target selectivity and cell membrane permeability, making them an attractive framework for modern peptide drug discovery. In terms of structural modification and functional improvement of polypeptide drugs, the head-to-tail cyclization modification of polypeptides is a very common structural optimization method. At present, a variety of methods have been developed to synthesize head-to-...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K1/06C07K1/04C07K1/20
CPCC07K1/06C07K1/04C07K1/20Y02P20/55
Inventor 方葛敏席痛快武梦朱汉英张燕妮
Owner ANHUI UNIVERSITY