Looking for breakthrough ideas for innovation challenges? Try Patsnap Eureka!

Fluorescent selective histone deacetylase inhibitor and preparation method and application thereof

A deacetylase and histone technology, applied in chemical instruments and methods, medical preparations containing active ingredients, organic chemistry, etc., can solve the problem of lack of HDAC6 subtype selectivity

Active Publication Date: 2018-11-13
SHANDONG UNIV
View PDF0 Cites 4 Cited by
  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Recently, a fluorescent HDACs inhibitor 4MS was reported (see Fleming, C.L. et al. Chemical Communications, 2015, 51, 7827), but this compound does not have HDAC6 subtype selectivity

Method used

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
View more

Image

Smart Image Click on the blue labels to locate them in the text.
Viewing Examples
Smart Image
  • Fluorescent selective histone deacetylase inhibitor and preparation method and application thereof
  • Fluorescent selective histone deacetylase inhibitor and preparation method and application thereof
  • Fluorescent selective histone deacetylase inhibitor and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0043] Example 1. Synthesis of Compounds 6a and 6b

[0044] synthetic route:

[0045]

[0046] Reagents and conditions: a) triethylamine, ethanol, microwave heating at 100°C; b) morpholine, 5-bisdiphenylphosphine-9,9-dimethylxanthene, bis(dibenzylideneacetone)palladium , cesium carbonate, toluene, 65°C; c) lithium hydroxide, water / THF; d) oxalyl chloride, N,N-dimethylformamide, dichloromethane, then hydroxylamine hydrochloride, triethylamine, water / THF.

[0047] Concrete synthesis method and steps are as follows:

[0048] Intermediate 3a: Methyl 4-((6-bromo-1,3-dioxo-1H-benzo[de]isoquinolin-2(3H)-yl)methyl)benzoate

[0049] Starting materials 6-Bromo-1H,3H-benzo[de]isochromene-1,3-dione (1,1.35g, 4.87mmol), methyl 4-(aminomethyl)benzoate Acid salt (2a, 4-982mg, 4.87mmol) and triethylamine (493mg, 4.87mmol) were dissolved in 20mL of ethanol, heated to 100°C for 45 minutes by microwave. The reaction solution was diluted with 100 mL of water, and extracted three times with...

Embodiment 2

[0064] Example 2. In vitro HDACs inhibitory activity evaluation experiment of target compounds

[0065] References [Duan, W.; Li, J.; Inks, E.S.; Chou, C.J.; Jia, Y.; Chu, X.; Li, X.; Xu, W.*; Zhang, Y.* Design, Synthesis and Antitumor Evaluation of Novel HistoneDeacetylase (HDAC) Inhibitors Equipped with Phenylsulfonylfuroxan Module as Nitric Oxide (NO) Donor. J. Med. Chem. 2015, 58 (10), 4325-4338.] Related methods to test the reported HDACs inhibition In vitro HDACs inhibitory activity of agent 4MS and compounds 6a and 6b of the present invention.

[0066] The test results (Table 1) show that the compound 6a of the present invention and the reported HDACs inhibitor 4MS have strong inhibitory activity on HDAC1, HDAC2, HDAC3 of class I subfamily and HDAC6 of class IIb subfamily, without subtype Selectivity; while compound 6b of the present invention shows strong subtype selectivity to HDAC6 of class IIb subfamily.

[0067] Table 1. Evaluation results of HDACs inhibitory acti...

Embodiment 3

[0070] Example 3. Target compound protein immunoblotting (Western blot) evaluation experiment

[0071] The HDACs inhibitory activity of the reported HDACs inhibitor 4MS and compounds 6a and 6b of the present invention in cells was evaluated by Western blot test.

[0072] Test principle: HDAC1, HDAC2 and HDAC3 of class I subfamily can deacetylate acetylated histone H4 (Ac-HH4), thereby reducing the protein level of Ac-HH4 in cells; HDAC6 of class IIb subfamily can deacetylate Tubulin (Ac-Tub) is deacetylated, thereby reducing the protein level of Ac-Tub in cells. Therefore, the inhibitory effect of the compound on intracellular HDACs can be evaluated by measuring the Ac-HH4 and Ac-Tub protein levels in the cells treated with the compound by Western blot assay.

[0073] Experimental materials and methods: Human non-small cell lung cancer A549 cells were treated with 4MS, 6a and 6b at a final concentration of 500nM respectively, and the cells were collected. The cells were lysed...

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to View More

PUM

No PUM Login to View More

Abstract

The invention discloses a fluorescent selective histone deacetylase inhibitor and a preparation method and application thereof. The fluorescent selective histone deacetylase inhibitor has a structuralgeneral formula (I) or (II) show in the description. The compound of formula (I) or (II) structure is applicable to the preparation of drugs to detect tissue distribution of histone deacetylase and cell and tissue imaging, and drugs to treat or diagnose diseases related to histone deacetylase dysfunction.

Description

technical field [0001] The invention relates to the technical field of organic compound synthesis and medical application, in particular to a fluorescent selective histone deacetylase inhibitor and its preparation method and application. Background technique [0002] Histone deacetylases (HDACs) are named for their early discovered biological function: deacetylation of the ε-amino group of N-terminal lysine residues of histone nucleosomes. Deacetylated histones are positively charged and bind more tightly to negatively charged DNA, which hinders the binding of various transcription factors to DNA, thereby inhibiting the transcription of various genes including tumor suppressor genes (see Wolffe, A.P.Science, 1996 ,272,371). With the in-depth study of the biological functions of HDACs, more and more non-histone proteins have been confirmed as substrates of HDACs, such as transcription factors, cytoskeletal proteins, molecular chaperones, etc. (see Glozak, M.A., et al. Gene, ...

Claims

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to View More

Application Information

Patent Timeline
no application Login to View More
IPC IPC(8): C07D221/14A61K31/5377A61P35/00A61P25/00A61P29/00A61P37/00C09K11/06G01N21/64
CPCC07D221/14C09K11/06C09K2211/1007C09K2211/1029C09K2211/1033G01N21/6486
Inventor 张颖杰
Owner SHANDONG UNIV
Who we serve
  • R&D Engineer
  • R&D Manager
  • IP Professional
Why Patsnap Eureka
  • Industry Leading Data Capabilities
  • Powerful AI technology
  • Patent DNA Extraction
Social media
Patsnap Eureka Blog
Learn More
PatSnap group products

Browse by: Latest US Patents, China's latest patents, Technical Efficacy Thesaurus, Application Domain, Technology Topic, Popular Technical Reports.

© 2024 PatSnap. All rights reserved.Legal|Privacy policy|Modern Slavery Act Transparency Statement|Sitemap|About US| Contact US: help@patsnap.com