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New purpose of perazine hydrochloride type compound

A perazine hydrochloride compound and the technology of perazine hydrochloride are applied in the new application field of the compound, and can solve the problems of poor specificity, small number of small molecular compounds and the like

Inactive Publication Date: 2019-11-01
TIANJIN UNIVERSITY OF SCIENCE AND TECHNOLOGY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Some compounds that promote TFEB expression have been used in clinical trials, but so far, the number of small molecule compounds that can induce TFEB activation has been found, and the specificity is poor

Method used

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  • New purpose of perazine hydrochloride type compound
  • New purpose of perazine hydrochloride type compound
  • New purpose of perazine hydrochloride type compound

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0029] Screening of Drugs to Promote Nuclear Importation of TFEB

[0030] ① When the TFEB-GFP stable cell line grows to the required density in the 6cm culture dish, the 96-well plate can be plated. Cells were collected, counted on a hemocytometer, and the concentration of the cell suspension was adjusted. 100 μL of the cell suspension was added to each well, plated so that the density of the cells to be tested was 8000 / well, and the edge of the 96-well plate was filled with PBS.

[0031] ②5% CO 2 After incubating at 37°C for 24 h, a final concentration of 10 μM of the drug (i.e. compound I10-[3-(4-methylpiperazin-1-yl)propyl]-2-(trifluoromethyl)phenothiazine disalt was added salt).

[0032] ③ 6 hours after dosing, fix with 4% paraformaldehyde at room temperature for 15-20 minutes.

[0033] ④ Discard 4% paraformaldehyde, wash with PBS three times, take photos with a fluorescent microscope or store at 4°C for subsequent photos.

[0034] like figure 1 The results show that ...

Embodiment 2

[0036] Screening for autophagy agonists

[0037] ① When the GFP-LC3 stable cell line grows to the desired density in the 6cm culture dish, the 96-well plate can be plated. Cells were collected, counted on a hemocytometer, and the concentration of the cell suspension was adjusted. 100 μL of the cell suspension was added to each well, plated so that the density of the cells to be tested was 8000 / well, and the edge of the 96-well plate was filled with PBS.

[0038] ②5% CO 2 After culturing at 37°C for 24 h, a final concentration of 10 μM drug (i.e. compound I10-[3-(4-methylpiperazin-1-yl)propyl]-2-(trifluoromethyl)phenothiazine disalt was added salt).

[0039] ③ 6 hours after dosing, fix with 4% paraformaldehyde at room temperature for 15-20 minutes.

[0040] ④ Discard 4% paraformaldehyde, wash with PBS three times, take photos with a fluorescent microscope or store at 4°C for subsequent photos.

[0041] like figure 2 The results showed that compound I could significantly i...

Embodiment 3

[0043] Effects of Compounds on Nuclear Importation Level of TFEB in HeLa Cells Detected by Nuclear Plasma Separation Technique

[0044] Using the cytoplasmic protein extraction reagents CER I and CER II, under the condition of low osmotic pressure, the cells are fully expanded, and then the cell membrane is destroyed to release the cytoplasmic protein, and then the nucleus is precipitated by centrifugation. The precipitate is the nucleus and the supernatant for cytoplasmic proteins.

[0045]① Inoculate an appropriate amount of cells in a 6-well plate and place at 37°C, 5% CO 2 conditions overnight.

[0046] ②Treat the cells with small molecule compounds and place at 37°C, 5% CO 2 Conditions continue to grow.

[0047] ③For adherent cells, digest the cells with trypsin containing EDTA, then add complete medium to stop the digestion, transfer to a 1.5mL centrifuge tube, centrifuge at 3000rpm for 5min, and collect the cells.

[0048] ④ Wash the collected cells once with PBS, p...

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Abstract

The invention provides a new purpose of a perazine hydrochloride type compound. The compound is 10-[3-(4-methyl piperazine-1-base) propyl]-2-(trifluoromethyl) phenothiazine dihydrochloride, can effectively promote TFEB nuclear translocation of a transcription factor and can effectively promote endogenous TFEB nuclear accumulation, besides, the process is independent of an mTOR signal channel and has protection effects on A beta damage, and the perazine hydrochloride type compound can be used as a potential autophagy excitant for treatment of neurodegenerative diseases.

Description

technical field [0001] The present invention relates to a new application of a compound, especially a new application of a perazine hydrochloride compound. Background technique [0002] Transcription Factor EB (TFEB) is the first identified basic-helix-loop-helix leucine zipper (bHLH-Zip) class of the MiTF / TFE family Transcription factors play an important regulatory role in the biosynthesis and metabolism of lysosomes, are important regulators of autophagy, and have a wide range of physiological functions. [0003] Studies have shown that TFEB binds to the promoter regions of many autophagy genes, inducing the biosynthesis of autophagosomes and the fusion of autophagosomes and lysosomes. Overexpression of TFEB enhanced the expression levels of 51 genes related to autophagy, while knockdown of TFEB downregulated their expression. TFEB regulates several key steps of the autophagy pathway, and has a direct regulatory effect on the activation of autophagy. [0004] Autophagy...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/496A61P25/28
CPCA61K31/496A61P25/28
Inventor 刁爱坡刘振兴蔺洁茹
Owner TIANJIN UNIVERSITY OF SCIENCE AND TECHNOLOGY
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