Cyclopeptide antitumor active compound and preparation method and application thereof

An anti-tumor activity, cyclic peptide technology, applied in the field of medicine, can solve the problems of poor membrane permeability, unstable conformation of anti-cancer drugs, weak anti-hydrolase ability, etc., to improve anti-tumor activity, improve enzyme stability and Antitumor activity, the effect of enhancing cell permeability

Active Publication Date: 2021-05-11
SHANGHAI UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] Aiming at the deficiencies of the prior art, the present invention provides a cyclic peptide anti-tumor active compound and its preparation method and application, which has the advantages of enhancing its cell permeability, improving enzyme stability and anti-tumor activity, and solving the existing anti-cancer Unstable drug conformation, poor membrane permeability and weak resistance to hydrolytic enzymes

Method used

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  • Cyclopeptide antitumor active compound and preparation method and application thereof
  • Cyclopeptide antitumor active compound and preparation method and application thereof
  • Cyclopeptide antitumor active compound and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0039] Example 1: The preparation method of cyclic peptide anti-tumor active compound, solid-phase synthesis of Ascaphin-8-1, the specific steps are as follows:

[0040] The amino resin protected by 9-fluorenylmethoxycarbonyl (Fmoc) is swelled, and the Fmoc must be removed before coupling. Replace the fourth and eighth amino acids with Fmoc-S5-OH, with 6-chlorobenzotriazole-1,1,3,3-tetramethyluronium hexafluorophosphate (HCTU), N,N - Diisopropylethylamine (DIPEA) is used as an activating reagent, and the above-mentioned protected amino acids are sequentially coupled, and each coupling takes 40 minutes. After each coupling of an amino acid, 20% piperidine / DMF should be used as the de-Fmoc reagent to de-Fmoc, 10 minutes each time. After the peptides were linked, phenylmethylene bis(triphenylhexylphosphine) ruthenium dichloride (first-generation Grubbs catalyst) was used as a cyclization reagent and reacted overnight. Use TFA / EDT / TIPs / Water (95:2:2:1, v / v / v / v) for 2 hours at ro...

Embodiment 2

[0041] Example 2: The preparation method of cyclic peptide anti-tumor active compound, solid-phase synthesis of Ascaphin-8-4, the specific steps are as follows:

[0042]The amino resin protected by 9-fluorenylmethoxycarbonyl (Fmoc) is swelled, and the Fmoc must be removed before coupling. The ninth amino acid was replaced with Fmoc-R8-OH, and the seventeenth amino acid was replaced with Fmoc-S5-OH. Using 6-chlorobenzotriazole-1,1,3,3-tetramethyluronium hexafluorophosphate (HCTU) and N,N-diisopropylethylamine (DIPEA) as activating reagents, the above protection Amino acids were coupled sequentially, 40 minutes per coupling. After each coupling of an amino acid, 20% piperidine / DMF should be used as the de-Fmoc reagent to de-Fmoc, 10 minutes each time. After the peptides were linked, phenylmethylene bis(triphenylhexylphosphine) ruthenium dichloride (first-generation Grubbs catalyst) was used as a cyclization reagent and reacted overnight. Use TFA / EDT / TIPs / Water (95:2:2:1, v / v / ...

experiment example

[0044] 1) Cell Biology Experiments

[0045] Prostate cancer bone metastasis cell line C4-2B was cultured in high glucose D-MEM containing 10% fetal bovine serum, 100 U / ml penicillin and 100 mg·L-1 streptomycin at 37°C, 5% CO2 Routine culture and passage in the incubator. Prostate cancer bone metastases cell line C4-2B was plated in a 96-well plate with 1000 cells per well, and peptides Ascaphin-8 and Ascaphin-8 of different concentrations (0, 3.125, 25, 12.5, 25, 50, 100um) were added the next day -1, Ascaphin-8-2, Ascaphin-8-3, Ascaphin-8-4. After 96 hours, add 10 μL of CCK8 reagent to each well and incubate at 37°C for 1 hour. Use a microplate reader (BioTek, Vermont, USA) to detect the absorbance value (OD) of each well at a wavelength of 450 nm, and calculate the cell viability (vital rate, VR) according to the OD value: VR=(OD value of the drug group-OD value of the blank group ) / (OD value of control group-OD value of blank group). Calculate the average VR of 3 paralle...

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Abstract

The invention relates to the technical field of medicines, and discloses a cyclopeptide antitumor active compound, and particularly relates to a cyclopeptide active molecule with a structure shown in a formula (I), the cyclopeptide active molecule with the structure shown in the formula (I) and pharmaceutically acceptable salt or ester thereof: GFKX1LLKX2X3AKX4LVKX5VLF.NH2(I), wherein X1 represents aspartic acid or (2R)-2-amino-2-methyl-6-heptenoic acid; X2 represents glycine or (2R)-2-amino-2-methyl-6-heptenoic acid; X3 represents alanine or (2R)-2-amino-2-methyl-9-decenoic acid; X4 represents alanine or (2R)-2-amino-2-methyl-6-heptenoic acid; X5 represents threonine or (2R)-2-amino-2-methyl-6-heptenoic acid; and paired (2R)-2-amino-2-methyl-6-heptenoic acid or (2R)-2-amino-2-methyl-9-decenoic acid in a fragment is cyclized through an olefin metathesis reaction. The cyclopeptide antitumor active compound and a preparation method and application thereof aim to enhance the cell permeability and improve the enzyme stability and antitumor activity.

Description

technical field [0001] The invention relates to the technical field of medicine, in particular to a cyclic peptide anti-tumor active compound and its preparation method and application. It has the activity of inhibiting the prostate cancer bone metastases cell line C4-2B and can be used to prepare related anti-cancer drugs. Background technique [0002] Prostate cancer is the most common cancer that occurs in men. Treatment for prostate cancer usually involves surgery, chemotherapy, and androgen deprivation therapy. However, these effective treatments are limited by drug resistance and cytotoxicity. In recent years, small-molecule drugs have been widely used in the treatment of major diseases such as tumors, but small-molecule drugs are also limited due to their large side effects and easy drug resistance. Peptide drugs have low toxicity and high antitumor activity, so they have received extensive attention. [0003] Ascaphin-8 (GFKDLLKGAAKALVKTVLF.NH2) is an α-helical ant...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K7/64A61K38/12A61P35/00
CPCC07K7/64A61P35/00A61K38/00
Inventor 胡宏岗丛薇刘婧何世鹏高飞汤华李英华
Owner SHANGHAI UNIV
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