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Histone deacetylase 8 selective degradation agent, preparation method and application of histone deacetylase 8 selective degradation agent in antitumor activity

A deacetylase and histone technology, which can be used in anti-tumor drugs, organic active ingredients, drug combinations, etc., and can solve problems such as untargeted histone deacetylase 8

Active Publication Date: 2022-04-29
SHENZHEN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Therefore, it is of great significance to develop degrading drugs that selectively target histone deacetylase 8, but there are no related reports on degrading drugs targeting histone deacetylase 8.

Method used

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  • Histone deacetylase 8 selective degradation agent, preparation method and application of histone deacetylase 8 selective degradation agent in antitumor activity
  • Histone deacetylase 8 selective degradation agent, preparation method and application of histone deacetylase 8 selective degradation agent in antitumor activity
  • Histone deacetylase 8 selective degradation agent, preparation method and application of histone deacetylase 8 selective degradation agent in antitumor activity

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Embodiment 1

[0061] This embodiment provides the preparation method of the above-mentioned histone deacetylase 8 selective degradation agent, specifically, the preparation method includes the following steps:

[0062] Synthesis of Compound 3a or 3b

[0063] The synthetic route is as follows:

[0064]

[0065] The specific steps are:

[0066] Weigh compound 1 (0.5g, 1.8mmol) and propargyl hydrochloride 2a (0.2g, 2.2mmol) and dissolve in 5mL N,N-dimethylacetylamine, then add N,N-diisopropyl Ethylamine (1.1 mL, 6.6 mmol), stirred at room temperature for 5 minutes. Then replace nitrogen, heat to 95°C, continue to react for 16h, and then cool to normal temperature. The reaction solution was extracted with ethyl acetate, and the organic phase was washed with saturated brine (30mLX3). The combined organic phases were concentrated and separated by silica gel column (V MeOH :V DCM =2%) was purified to obtain compound 3a (0.45 g) as a yellow solid with a yield of 83%.

[0067] The structur...

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Abstract

The invention discloses a histone deacetylase 8 selective degradation agent, a preparation method and application of the histone deacetylase 8 selective degradation agent in antitumor activity, and relates to the technical field of drug design and synthesis. The histone deacetylase 8 selective degradation agent provided by the invention can obviously and selectively degrade the deacetylase 8 in tumor cells in a concentration-dependent manner without influencing other types of deacetylases, so that the histone deacetylase 8 selective degradation agent can be used for preparing medicines for preventing or treating diseases related to abnormal activity or expression of HDAC8; particularly, the compound has a value in the aspect of anti-tumor active drugs.

Description

technical field [0001] The invention relates to the technical field of drug design and synthesis, in particular to a histone deacetylase 8 selective degradation agent, a preparation method and its application in antitumor activity. Background technique [0002] Protein degradation targeting chimera (PROTAC) technology is a novel strategy to chemically induce target protein degradation through the ubiquitin-proteasome pathway. PROTAC is a bifunctional molecule connected by a target protein ligand and an E3 ubiquitin ligase ligand through an appropriate linker chain, which can simultaneously recruit target protein and E3 ubiquitin ligase, thereby inducing ubiquitin degradation of the target protein. Wide application prospects. [0003] Compared with traditional small molecule inhibitors, PROTAC technology has the following significant advantages: From the perspective of mode of action, PROTAC molecules are fundamentally different from traditional inhibitors. Traditional inhi...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/14A61K31/4439A61P35/00
CPCC07D401/14A61P35/00
Inventor 朱卫国黄金波张俊许文超
Owner SHENZHEN UNIV