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Cyclo(Phe-Pro-lle-Phe-Pro-Pro-Leu-Val)peptide preparation method

A fmoc-phe-oh, cyclization reaction technology, applied in the preparation methods of peptides, chemical instruments and methods, peptides, etc., can solve problems such as restricting production and application, high cost, and low content.

Inactive Publication Date: 2018-01-05
ANHUI UNIVERSITY OF TECHNOLOGY AND SCIENCE
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003] But so far, the acquisition of Samoamide A is limited to extraction from microorganisms, and there are problems such as low content, complicated separation and purification, and high cost, which restrict its further production and application.

Method used

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  • Cyclo(Phe-Pro-lle-Phe-Pro-Pro-Leu-Val)peptide preparation method

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preparation example Construction

[0023] The invention provides a method for preparing a cyclic (phenylalanine-proline-isoleucine-phenylalanine-proline-proline-leucine-valine) peptide, comprising:

[0024] 1) The base resin, Fmoc-Phe-OH, and N,N-diisopropylethylamine with the structure shown in formula (I) are contacted in a solvent to prepare a compound with the structure shown in formula (II). Grade resin, then by methanol capping primary resin, then remove the Fmoc of the primary resin by Fmoc eluent elution, finally through piperidine deprotection to obtain the secondary resin of structure shown in formula (III);

[0025] 2) The secondary resin is subjected to multiple continuous modification reactions with various modified amino acids in turn to obtain a tertiary resin with a structure shown in formula (IV); each step of the modification reaction is: the resin and the modified amino acid are mixed in N , in the presence of N-diisopropylethylamine, solvent and HATU, carry out contact reaction, then remove ...

Embodiment 1

[0055]

[0056] 1) Soak 2-chlorotrityl chloride resin (2g, represented by formula I-1) in dichloromethane (1mL) for 30min, add N-fluorenylmethoxycarbonylphenylalanine (1029.4mg, 2.65mmol ), DIPEA (1390uL, 7.95mmol), stirred and reacted at 25°C for 1h, and the resulting N-fluorenylmethoxycarbonylphenylalanine-2-chlorotrityl chloride resin (shown in formula II-1) was added to methanol To seal the head, rinse 3 times with DCM and DMF respectively (15-25mL of DCM and DMF each time). After deprotection with 20% by weight of piperidine (20 mL) at 25° C. for 30 min to remove Fmoc, wash with DCM and DMF 3 times each (15-25 mL for each DCM and DMF) to obtain phenylalanine-2-chlorotris Benzyl chloride resin (shown in formula III-1).

[0057] 2) N-Fremoxyproline (2692.5mg, 7.95mmol), DIPEA (1390uL, 7.95mmol), HATU (1517mg, 3.99mmol), and DCM (20mL) were added to phenylalanine-2- In chlorotrityl chloride resin, stir and react at 25°C for 1h, remove the filtrate, wash 3 times with DCM...

Embodiment 2

[0071] Carry out according to the method for embodiment 1 and obtain cyclic (phenylalanine-proline-isoleucine-phenylalanine-proline-proline-leucine-valine) peptide (total yield 48.8%, weight 1017.56mg), the difference is that the amount of Fmoc-Phe-OH in step 1) is 3mmol, the amount of Fmoc-Pro-OH in step 2) is 9mmol, and the amount of Fmoc-Ile-OH in step 2) The consumption of OH is 9mmol, the consumption of Fmoc-Phe-OH in step 2) is 9mmol, the consumption of the Fmoc-Pro-OH that adds for the first time in step 2) is 9mmol, the Fmoc-Pro-OH that adds for the second time in step 2) The amount of Pro-OH used is 9 mmol, the amount of Fmoc-Leu-OH used in step 2) is 9 mmol, and the amount used of Fmoc-Val-OH in step 2) is 9 mmol.

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Abstract

The invention discloses a cyclo(Phe-Pro-lle-Phe-Pro-Pro-Leu-Val)peptide preparation method. The preparation method comprises 1) contacting a matrix resin, Fmoc-Phe-OH and DIPEA in a solvent for a reaction to obtain a primary resin, removing Fmoc through methanol end blocking and elution and carrying out piperidine deprotection to obtain a secondary resin, 2) carrying out continuous modification onthe secondary resin orderly with a plurality of modified amino acids multiple times to obtain a tertiary resin, wherein each modification reaction process comprises that the resin and the modified amino acids contact and undergo reactions in the presence of DIPEA, a solvent and HATU, removing Fmoc through elution and carrying out piperidine deprotection, 3) removing the resin group in the tertiary resin through a resin eluent so that linear octapeptide is obtained, and 4) carrying out liquid phase cyclization on the linear octapeptide in the presence of a solvent, PyBOP, HOBt and DIPEA to obtain cyclopeptide. The preparation method realizes synthesis of cyclopeptide.

Description

technical field [0001] The present invention relates to the preparation method of cyclic peptide, in particular, relates to cyclic (phenylalanine-proline-isoleucine-phenylalanine-proline-proline-leucine-valine) Methods of Peptide Preparation. Background technique [0002] Cyclic peptide Samoamide A (cyclic (phenylalanine-proline-isoleucine-phenylalanine-proline-proline-leucine-valine) peptide or cyclic (Phe-Pro- lle-Phe-Pro-Pro-Leu-Val) peptide) is a polypeptide extracted from the marine cyanobacteria Symploca spp, an octacyclic peptide composed of Phe-Pro-lle-Phe-Pro-Pro-Leu-Val (05Jan 2017,80(3):625-633). Inhibition of the enzyme dipeptidyl peptidase (CD26, DPP4) at the allosteric binding site of cancer cells by Samoamide A was shown to be in vitro in several human cancer cell lines in conventional cell culture and domain inhibition bioassays Toxic activity. [0003] But so far, the acquisition of Samoamide A is limited to extraction from microorganisms, and there are ...

Claims

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Application Information

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IPC IPC(8): C07K7/64C07K1/04C07K1/06
Inventor 陶玉贵张驰朱龙宝葛飞李婉珍宋平朱龙龙张旭
Owner ANHUI UNIVERSITY OF TECHNOLOGY AND SCIENCE
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