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Method for efficient synthesis of Stylissatin A natural cyclo-heptapeptide

A natural cyclic and heptapeptide technology, which is applied in the field of high-efficiency synthesis of StylissatinA natural cyclic heptapeptide, can solve the problem of low content of StylissatinA, and achieve the effect of simple synthesis process and high yield

Inactive Publication Date: 2016-08-03
SECOND MILITARY MEDICAL UNIV OF THE PEOPLES LIBERATION ARMY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

In the existing technology, the cyclic heptapeptide is isolated from the sponge, but the content of Stylissatin A extracted from the sponge is particularly low, and only 3mg of the target compound can be extracted from 840g of the sponge raw material
Therefore, a high-efficiency solid-phase synthesis method for the natural cyclic heptapeptide of StylissatinA was developed to make up for the defect of less natural extraction and provide a material basis for further activity research. However, there has been no report on this type of method.

Method used

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  • Method for efficient synthesis of Stylissatin A natural cyclo-heptapeptide
  • Method for efficient synthesis of Stylissatin A natural cyclo-heptapeptide
  • Method for efficient synthesis of Stylissatin A natural cyclo-heptapeptide

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Experimental program
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Effect test

Embodiment 1

[0042] The retrosynthetic route analysis of the natural cyclic heptapeptide of embodiment 1 StylissatinA

[0043] StylissatinA is a proline-rich cyclic heptapeptide with 4 different amino acids. Through preliminary experiments, we optimized and selected phenylalanine and isoleucine as the cyclization sites, isoleucine as the amino terminal of the linear peptide, and phenylalanine as the carboxyl terminal of the linear peptide. Linear peptides are synthesized by solid-phase synthesis, and the linear peptides are cyclized in liquid phase. The final crude peptide product is separated and purified by preparative liquid phase to obtain the final target compound. Synthetic strategy of StylissatinA.

[0044]

Embodiment 2

[0045] The solid-phase synthesis process of embodiment 2 linear peptide 6

[0046] The linear peptide compound 6 was prepared using the synthetic route shown below. Wherein compound 2 represents 2 chlorotrityl resins

[0047]

[0048] a.Fmoc-Leu-OH, dimethylformamide, dichloromethane, N,N-diisopropylethylamine, 1h; b. 20% pyridine in dimethylformamide, 15 minutes; c.Fmoc- AA-OH, 1-hydroxybenzotriazole, N,N-diisopropylethylamine, dimethylformamide, 1h; d. acetic acid / trifluoroethanol / dichloromethane (1:2:16), 3h.

[0049]Specific steps are as follows:

[0050] (1) Weigh 500 mg of 2-chlorotrityl resin (the degree of substitution is 0.33 mmol / g), place it in a dry solid-phase synthesis tube, and wash it with dimethylformamide (DMF) and dichloromethane (DCM) respectively Resin each 5 times, then add dichloromethane to soak the resin for 15min, so as to make the resin expand and facilitate the reaction.

[0051] (2) Then take out the methylene chloride, take 0.2mmol of Fmoc...

Embodiment 3

[0056] The cyclization of embodiment 3 linear peptide 6

[0057] The target compound was prepared by cyclization using the synthetic route shown below.

[0058]

[0059] a. Benzotriazol-1-yl-oxytripyrrolidinylphosphonium hexafluorophosphate, hydroxybenzotriazole, N,N-diisopropylethylamine, N-methylpyrrolidone, dichloromethane, 0°C. Overnight; b. Trifluoroacetic acid / phenol / water / triisopropylsilane (88:5:5:2, v / v) stirred and reacted for 3 hours.

[0060] Specific steps are as follows:

[0061] (1) Weigh 260mg (0.5mmol) of benzotriazol-1-yl-oxytripyrrolidinylphosphonium hexafluorophosphate, 68mg (0.5mmol) of 1-hydroxybenzotriazole, N,N-diiso Add 172ul (1mmol) of propylethylamine to a 500ml round bottom flask, then add a little dichloromethane, add 1-2ml N-methylpyrrolidone, dissolve the sample by ultrasonic, then add 150ml anhydrous dichloromethane to the round bottom flask , placed in a cold well previously cooled to 0°C, stirred for about 10 minutes, and the temperature...

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Abstract

The invention relates to a method for efficient synthesis of Stylissatin A natural cyclo-heptapeptide. The method mainly comprises the steps of 1, analysis of a Stylissatin A natural cyclo-heptapeptide retrosynthesis route; 2, solid-phase synthesis of linear chain peptide 6; 3, cyclization of linear chain peptide 6; 4, efficient liquid-phase separation of the product cyclopeptide. The method has the advantages that synthesis is easy and yield is high. The method can overcome the defect of small natural extraction amount and provides a material basis for further activity study.

Description

technical field [0001] The invention relates to the technical field of compound synthesis, in particular to a preparation method for efficiently synthesizing Stylissatin A natural cyclic heptapeptide. Background technique [0002] Naturally occurring cyclic peptides have high pharmaceutical value due to their unique chemical structures and strong biological activities. Unlike linear peptides, cyclic peptides are more stable in vivo, have better fat solubility and membrane permeability, and show higher specificity for targets. These bioactive cyclic peptides can serve as promising drug candidates. Recently, a series of proline-rich cyclic peptides have been isolated from marine organisms, such as rollamides, axinastatins, phakellistatins, etc. However, the content of the above-mentioned cyclic peptides isolated from marine organisms is extremely low. In order to further study their biological activity and structure-activity relationship, many researchers focus on the synthe...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K7/64C07K1/06C07K1/04
CPCC07K7/64Y02P20/55
Inventor 李玉磊董欣杜红丽赵红霞李娜刘超吴也闫芳
Owner SECOND MILITARY MEDICAL UNIV OF THE PEOPLES LIBERATION ARMY