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Preparation method of homocyclopeptide cyclo-(ala)4

A technology of cyclic peptide and resin, which is applied in the field of cyclic peptide compound cyclic peptide Cyclo-4 and its synthesis and preparation technology, to achieve good fat solubility and stability in vivo, high synthesis efficiency, good regularity and multi-directional symmetry.

Active Publication Date: 2021-03-16
INST OF NUCLEAR PHYSICS & CHEM CHINA ACADEMY OF
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0004] In recent years, 2-(7-azobenzotriazole)-tetramethyluronium hexafluorophosphate (HATU), benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphate Fluorophosphate (HBTU), 1-hydroxybenzotriazole (HOBt), O-benzotriazole-N,N,N',N'-tetramethyluronium tetrafluoroboric acid (TBTU) and other benzo The use of azole organic condensing agents has provided great help for the research of cyclic peptide synthesis methods; but so far, it has been mainly used in the synthesis of RGD cyclic peptides (cyclic peptides containing arginine-glycine-aspartic acid) ( Wang Xiping. RGD synthesis and preparation process. CN, 103588863 B[P]. 2013-11-15.), there is no related new cyclic peptide Cyclo-(Ala) 4 , especially the reports on related processes of its chemical preparation method

Method used

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  • Preparation method of homocyclopeptide cyclo-(ala)4
  • Preparation method of homocyclopeptide cyclo-(ala)4
  • Preparation method of homocyclopeptide cyclo-(ala)4

Examples

Experimental program
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Effect test

Embodiment 1

[0027] A homocyclic peptide Cyclo-(Ala) 4 preparation methods, including:

[0028]Step 1. Soak 2-chlorotrityl chloride resin with dichloromethane and shake for 30 minutes; remove the solvent after the resin is swollen, and take a three-fold molar excess of alanine with fluorenyl moxycarbonyl protecting group in the resin 1. N,N-diisopropylethylamine is added to the resin in a ten-fold molar excess, then DMF is added to dissolve it, and the reaction is shaken at room temperature for 30 minutes; then methanol is added to incubate for 20 minutes; the reactive sites on the resin are sealed; Wash the resin repeatedly with DMF and methanol solvent and remove the solvent. The first amino acid is connected to the resin; After fully washing with ethanol, add one drop each of 5% ninhydrin ethanol solution, 0.3% ascorbic acid solution, and 60% phenol solution, and heat to 110°C and keep it warm for 5 minutes. If the resin color turns dark blue, then It shows that the amino acid has bee...

Embodiment 2

[0033] A homocyclic peptide Cyclo-(Ala) 4 preparation methods, including:

[0034] Step 1. Soak 2-chlorotrityl chloride resin with dichloromethane and shake for 30 minutes; remove the solvent after the resin is swollen, and take a three-fold molar excess of alanine with fluorenyl moxycarbonyl protecting group in the resin 1. N,N-diisopropylethylamine is added to the resin in a ten-fold molar excess, then DMF is added to dissolve it, and the reaction is shaken at room temperature for 30 minutes; then methanol is added to incubate for 20 minutes; the reactive sites on the resin are sealed; Wash the resin repeatedly with DMF and methanol solvent and remove the solvent. The first amino acid is connected to the resin; After fully washing with ethanol, add one drop each of 5% ninhydrin ethanol solution, 0.3% ascorbic acid solution, and 60% phenol solution, and heat to 105°C for 5 minutes at the same time. If the resin color turns dark blue, then It shows that the amino acid has be...

Embodiment 3

[0039] A homocyclic peptide Cyclo-(Ala) 4 preparation methods, including:

[0040] Step 1. Soak 2-chlorotrityl chloride resin with dichloromethane and shake for 30 minutes; remove the solvent after the resin is swollen, and take a three-fold molar excess of alanine with fluorenyl moxycarbonyl protecting group in the resin 1. N,N-diisopropylethylamine is added to the resin in a ten-fold molar excess, then DMF is added to dissolve it, and the reaction is shaken at room temperature for 30 minutes; then methanol is added to incubate for 20 minutes; the reactive sites on the resin are sealed; Wash the resin repeatedly with DMF and methanol solvent and remove the solvent. The first amino acid is connected to the resin; After fully washing with ethanol, add one drop each of 5% ninhydrin ethanol solution, 0.3% ascorbic acid solution, and 60% phenol solution, and heat to 105°C for 5 minutes at the same time. If the resin color turns dark blue, then It shows that the amino acid has be...

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Abstract

The invention discloses a preparation method of a homogeneous cyclic peptide Cyclo-(Ala)4. The preparation method comprises the steps: (1) allowing resin to react and be connected with alanine with aprotecting group to form resin connected with alanine, (2) conducting continuous condensation on alanine connected with the resin and alanine with the protecting group to form resin connected with a linear chain peptide, (3) cutting the linear chain peptide from the resin for end-to-end cyclization to form a cyclic peptide crude product, and (4) purifying and storing the cyclic peptide. Cyclo-(Ala)4 prepared by the method is in a homogeneous cyclic peptide structure formed by single amino acid, has a structure extremely similar to that of a crown ether compound; molecules having good regularity and multidirectional symmetry in structure can be self-assembled into an ion channel or a nano tube more easily as a drug carrier, a membrane channel, a molecular element and the like; no free aminogroup or carboxyl group is available in the molecules of the cyclic peptide, so that the cyclic peptide has extremely good liposolubility and biological in-vivo stability; at the same time, the method is reasonable in technology and simple in operation; the synthesis efficiency is higher.

Description

technical field [0001] The invention belongs to the technical field of polypeptide synthesis, and relates to a chemical preparation method of cyclic peptide compounds, in particular to the cyclic peptide compound cyclic peptide Cyclo-(Ala) 4 and its synthetic preparation process. Background technique [0002] Cyclic peptides have a high structural similarity with ordinary chain peptides in terms of structural composition, but because the amino acid residues in the main structure participate in the connection to form a ring, the free carboxyl, amino and other hydrophilic groups in the molecule disappear or decrease. It reduces its polarity, enhances its fat solubility, reduces its sensitivity to ammonia / carboxypeptidase in vivo, and increases its stability in vivo; at the same time, the degree of freedom of peptide chain movement decreases, and it has a relatively stable and definite conformation in solution. The probability of fitting with the receptor is significantly impr...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07K7/64C07K1/06C07K1/04C07K1/16
CPCY02P20/55
Inventor 宋宏涛魏洪源
Owner INST OF NUCLEAR PHYSICS & CHEM CHINA ACADEMY OF
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