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Cyclic peptide anti-tumor activity compound and preparation method therefor and application of cyclic peptide anti-tumor activity compound

A technology with anti-tumor activity and cyclic peptides, which is applied in the field of medicine, can solve the problems of weak anti-hydrolytic enzyme ability, unstable conformation, and poor membrane penetration ability, so as to improve structural rigidity, enhance cell permeability, and improve enzyme stability. and antitumor activity

Pending Publication Date: 2020-09-15
SHANGHAI UNIV
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] In view of the deficiencies in the prior art, the present invention provides cyclic peptide anti-tumor active compounds and their preparation methods and applications, which have the advantages of enhancing their cell permeability, improving enzyme stability and anti-tumor activity, and solve the existing anti-cancer The drug has the problems of unstable conformation, poor membrane permeability and weak resistance to hydrolytic enzymes

Method used

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  • Cyclic peptide anti-tumor activity compound and preparation method therefor and application of cyclic peptide anti-tumor activity compound
  • Cyclic peptide anti-tumor activity compound and preparation method therefor and application of cyclic peptide anti-tumor activity compound
  • Cyclic peptide anti-tumor activity compound and preparation method therefor and application of cyclic peptide anti-tumor activity compound

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0042] Example 1: The preparation method of cyclic peptide anti-tumor active compound, solid-phase synthesis of A4K14-Citropin1.1-Sp1, the specific steps are as follows:

[0043]The amino acid α-amino group is protected with 9-fluorenylmethoxycarbonyl (Fmoc), and the side chain of the amino acid is protected: the side chain protection group of Ser is tert-butyl (tBu), and the side chain protection group of Lys is tert-butoxycarbonyl (Boc), wherein the amino acids at the second and fifth positions are replaced with Fmoc-S5-OH, and 6-chlorobenzotriazole-1,1,3,3-tetramethyluronium hexafluorophosphate (HCTU ), N,N-diisopropylethylamine (DIPEA) as the activation reagent, the above-mentioned protected amino acids were coupled sequentially, each coupling was 40 minutes, and 20% piperidine / DMF was used as the de-Fmoc reagent, each time was 10 minutes , after the polypeptide is connected, phenylmethylene bis(triphenylhexylphosphine) ruthenium dichloride (the first generation Grubbs cat...

Embodiment 2

[0044] Example 2: The preparation method of cyclic peptide anti-tumor active compound, solid-phase synthesis of A4K14-Citropin1.1-Sp6, the specific steps are as follows:

[0045] The amino acid α-amino group is protected with 9-fluorenylmethoxycarbonyl (Fmoc), and the side chain of the amino acid is protected: the side chain protection group of Ser is tert-butyl (tBu), and the side chain protection group of Lys is tert-butoxycarbonyl (Boc), wherein the second position is replaced by Fmoc-R8-OH, the ninth amino acid is replaced by Fmoc-S5-OH, and 6-chlorobenzotriazole-1,1,3,3-tetramethylurea Hexafluorophosphate (HCTU) and N,N-diisopropylethylamine (DIPEA) were used as activating reagents, and the above-mentioned protected amino acids were coupled sequentially, each coupling was 40 minutes, and 20% piperidine / DMF was used as de-Fmoc Reagents, 10 minutes each time, after the peptide is connected, phenylmethylene bis(triphenylhexylphosphine) ruthenium dichloride (first-generation ...

experiment example

[0047] 1) Cell Biology Experiments

[0048] CCK-8 tumor suppression experiment in vitro: Prostate cancer cell C42B was cultured in high-glucose D-MEM containing fetal bovine serum (10%), penicillin (100KU·L-1) and streptomycin (100mg·L-1) based on 37 C42B cells in the logarithmic growth phase were seeded in a 96-well plate at a density of 2 × 104mL-1 in a 5% CO2 incubator, with 100μL per well, and 3 replicate wells for each group. The peptide concentration was 0.39, 0.78, 1.56, 3.125, 6.25, 12.5, 25, 50 μM concentrations act on the cells. After the cells are cultured for 96 hours, add 100 μL of complete medium containing 10% CCK-8 reagent to each well, and incubate at 37°C in a 5% CO2 incubator in the dark After 2h, use a microplate reader (BioTek, Vermont, USA) to detect the absorbance value (OD) of each well at a wavelength of 450nm, and calculate the cell viability (vitalrate, VR) according to the OD value: VR=(OD value of drug group-blank group OD value) / (control group OD...

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Abstract

The invention relates to the technical field of medicine, and discloses a cyclic peptide anti-tumor activity compound, in particular to a cyclic peptide active molecule with a structure shown by a formula (I). According to the cyclic peptide active molecule with the structure of the formula (I) and pharmaceutically acceptable salt or ester thereof: GX1FAX2X3KKX4ASVX5KX6L (I), X1 represents leucineor (2R)-2-amino-2-methyl-6-heptenoic acid or (2R)-2-amino-2- methyl-9-decenoic acid; X2 represents valine or (2R)-2-amino-2-methyl-6-heptenoic acid; X3 represents isoleucine or (2R)-2-amino-2-methyl-6-heptenoic acid; X4 represents valine or (2R)-2-amino-2-methyl-6-heptenoic acid; X5 represents isoleucine or (2R)-2-amino-2-methyl-6-heptenoic acid; X6 represents glycine or (2R)-2-amino-2-methyl-6-heptenoic acid; and coupled (2R)-2-amino-2-methyl6-heptenoic acids or (2R)-2-amino-2-methyl-9-decenoic acids in a fragment are cyclized through olefin metathesis. The cyclic peptide anti-tumor activitycompound and a preparation method therefor and application of the cyclic peptide anti-tumor activity compound aim to enhance the cell permeability of the cyclic peptide anti-tumor activity compound,and to improve enzyme stability and anti-tumor 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 prostate cancer cell C42B and can be used to prepare related anti-cancer drugs. Background technique [0002] The World Health Organization statistics report shows that in 2008, there were more than 12 million cancer patients in the world, and the death rate was as high as 7 million; by 2015, the number of cancer patients was as high as 15 million, and the death rate reached 8.8 million. It is a public health problem and is the main cause of death. At present, small molecule anticancer drugs have achieved remarkable results in clinical application, but their accompanying liver, kidney and gastrointestinal toxicity, hair loss, diarrhea and dyspnea, etc. Side effects greatly limit its application, and peptide drugs have received more and more attention due to t...

Claims

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Application Information

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IPC IPC(8): C07K7/56A61K38/12A61P35/00
CPCC07K7/56A61P35/00A61K38/00
Inventor 胡宏岗丛薇汪楠何世鹏高飞马飞
Owner SHANGHAI UNIV
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