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A kind of olefin thioether staple peptide and its preparation method and application

A technology of olefin thioether and staple peptide, which is applied in the field of medicine, can solve the problems of staple peptide diastereoisomer impurities, limit the promotion and application of staple peptide, and difficult separation and purification, and achieve convenient synthesis and stability in vivo The effect of long resistance and good membrane permeability

Active Publication Date: 2022-04-12
ACADEMY OF MILITARY MEDICAL SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Because it has a chiral center, chiral synthesis or preparation by resolution is required, and when synthesizing stapled peptides, it is necessary to introduce a side chain olefin at the α position of the amino acid to form a fully substituted structure at the α position, which requires the α-form The base-α-alkenyl amino acid itself must have high optical purity, otherwise the synthesized staple peptide will have diastereoisomer impurities, which will cause difficulties in separation and purification in the later stage
At present, the cost of preparing α-methyl-α-alkenyl unnatural amino acids with high optical purity by chiral synthesis or resolution is very high, which limits the promotion and application of this type of stapled peptide

Method used

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  • A kind of olefin thioether staple peptide and its preparation method and application
  • A kind of olefin thioether staple peptide and its preparation method and application
  • A kind of olefin thioether staple peptide and its preparation method and application

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preparation example Construction

[0032] The methods for the preparation of stapled peptides reported in the existing literature all start from amino acids, first protect them, then cyclize, selectively introduce olefin side chains, and then open the rings, remove the protecting groups, etc., generally need seven or eight steps of reaction to prepare get. Because of its long synthetic route and expensive raw materials, the application of its products is limited. In addition, the linear polypeptide in the early staple peptide is to cut out a functional polypeptide in the protein, and then use the existing amino acids in this polypeptide to select the binding site. In this way, the optional binding site is very popular. Restrictions are not conducive to the formation of the staple bridge.

[0033] Cysteine ​​contains a sulfhydryl functional group, which is often used as a binding site in the synthesis of stapled peptides, but the existing methods all directly bind cysteine ​​in linear polypeptides by chemical m...

Embodiment 1

[0045] Example 1: Synthesis of (XL-1)

[0046] (1) unnatural amino acid Fmoc-Cys (C 3 -C 5 Synthesis of -ene)-OH

[0047] Synthesis of Fmoc-Cys(Allyl)-OH

[0048] 2.98g (24.7mmol) of L-cysteine ​​was placed in a 250mL flask, 75mL of ethanol was added, ice bathed, 3.50g (87.5mmol) of sodium hydroxide was dissolved in 45mL of water and added to the reaction system. After stirring at room temperature for 10 minutes, 3.30 g (24.7 mmol) of 3-bromopropene was added, and the stirring reaction was continued for 3 hours. Glacial acetic acid was added until the pH of the reaction system = 5.5, a large amount of white solids were precipitated, filtered and dried in vacuo to obtain 2.50 g of solids. This solid was placed in a 100mL single-necked flask, 50mL of water was added, 1.90g of sodium bicarbonate (22.6mmol) was added to the reaction system in batches, 6.54g of 9-fluorenylmethylsuccinimidyl carbonate (Fmoc-OSu) ( 19.4mmol) was dissolved in 25mL tetrahydrofuran, added into th...

Embodiment 2

[0057] Example 2: Synthesis of (XL-2)

[0058] Carry out by the method for embodiment 1. 0.30 g Wang resin (loading rate 0.63 mmol / g, 0.19 mmol) was synthesized by standard solid-phase peptide synthesis method. After separation and purification, 38 mg of the target stapled peptide (named XL-2) was obtained. HR MS m / z: for [M] + , calculated 1289.641, found 1289.604.

[0059] Using the same preparation process as XL-2, only changing Fmoc-Cys(Butyl)-OH to Fmoc-Cys(Allyl)-OH, the compound of formula (4) was obtained and confirmed to be the compound of formula (4).

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Abstract

The invention discloses an olefin thioether staple peptide, which is characterized in that the structure of the olefin thioether staple peptide is formula (I), wherein X is a polypeptide composed of n natural amino acids, and n is 2-4 integer, m 1 and m 2 Integers in the numerical range of 1-3 respectively, C is the α-carbon atom in cysteine, Y 1 A polypeptide consisting of 3‑8 natural amino acids; preferably, Y 2 A polypeptide consisting of 2-5 natural amino acids or any one of natural amino acids. These staple peptide molecules show obvious anti-proliferation activity in different tumor cells, and can be used for the treatment of tumor diseases.

Description

technical field [0001] The invention belongs to the field of medicine, and in particular relates to an olefin thioether staple peptide and its preparation method and application. [0002] technical background [0003] Peptide molecules have received extensive attention in drug development due to their advantages of high activity, low toxicity, and low dosage. However, few peptide molecules can be marketed as peptide drugs. The main reason is that most peptide drugs are linear peptides, which have the disadvantages of poor cell membrane penetration and easy decomposition in vivo due to unstable spatial conformation. [0004] The reason why the spatial conformation of polypeptide drugs is not fixed is that α-helix is ​​the most common secondary structural unit in proteins, and plays an extremely important role in the interaction between proteins and proteins and between proteins and DNA. If the α-helical structure is intercepted from the protein to synthesize short peptide fra...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07K7/06C07K7/08C07K1/06C07K1/04A61K38/08A61K38/10A61P35/00
CPCC07K7/06C07K7/08A61P35/00A61K38/00
Inventor 彭涛夏亮王林王刚张首国孙云波刘曙晨温晓雪
Owner ACADEMY OF MILITARY MEDICAL SCI
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