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4-substituted naphthalimide compound and use thereof

A technology of naphthalimide and compound, applied in the field of 4-thiomorpholinyl-1,8-naphthalimide and derivatives thereof, can solve the problems of insufficient similarity, unsatisfactory effect, toxic and side effects and the like

Active Publication Date: 2018-01-05
DALIAN UNIV OF TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

They are all BH3 analogs, but they all have serious deficiencies
Gossypol BH3 has insufficient similarity and is not a specific BH3 analogue, so it has certain toxic and side effects
Although ABT-263 is a BH3 analogue, it cannot interact with Mcl-1 and cannot broadly inhibit Bcl-2 family proteins. During the experiment, it was found that its effect on cancer cells with high expression of Mcl-1 was not ideal and serious resistance
However, terphenyl compounds only show micromolar-level affinity in in vitro competitive binding experiments, and such affinity is far from being able to efficiently induce apoptosis.

Method used

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  • 4-substituted naphthalimide compound and use thereof
  • 4-substituted naphthalimide compound and use thereof
  • 4-substituted naphthalimide compound and use thereof

Examples

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preparation example Construction

[0043] The present invention further provides the preparation method of described 4-substituted naphthalimide compounds, comprising the steps of:

[0044] (1) 4-bromo-naphthalic anhydride and R 1H reacts in the presence of an acid-binding agent according to a molar ratio of 1:1.2-1.5 to obtain compound III, the reaction time is 6-12h, the reaction temperature is 80-150°C, the reaction solvent is DMF, and the acid-binding agent is triethylamine; preferably React under nitrogen protection;

[0045]

[0046] (2) Compound III and NH 2 、C 1-6 Alkylamine or (OH, OCH 3 , I, Br, Cl, NO 2 , NH 2 , NHCH 3 , N(CH 3 ) 2 、CH(OCH 3 ) 2 , CN, COOCH 3 、COOC 2 h 5 , R 3 ) replaced by C 1-6 Alkylamine reacts in the presence of an acid-binding agent according to a molar ratio of 1:2-1:5 to prepare Compound I, wherein R 2 (respectively) H, C 1-6 Alkyl, or (OH, OCH 3 , I, Br, Cl, NO 2 , NH 2 , NHCH 3 , N(CH 3 ) 2 、CH(OCH 3 ) 2 , CN, COOCH 3 、COOC 2 h 5 , R 3 ) repla...

Embodiment 1

[0074] Example 1: Preparation of N-ethyl-4-benzylamino-1,8-naphthalimide (compound 1)

[0075]

[0076] (1) Synthesis of Intermediate A1

[0077] Take 1.39g (5mmol) 4-bromo-1,8-naphthalic anhydride, 0.589g (5.5mmol) benzylamine, 0.556g triethylamine, add 15mL DMF, react at 85°C for 6h, cool to room temperature and pour 150mL water, filter with suction. The resulting solid was recrystallized from petroleum ether / ethyl acetate to obtain intermediate A1 (4-benzylamino-1,8-naphthalic anhydride) as a yellow solid with a yield of 80%.

[0078] (2) Synthesis of compound 1

[0079] Take 303mg of intermediate A1, 225mg of ethylamine and 506mg of triethylamine, add 10mL of ethanol, reflux under the protection of nitrogen, spot the plate to follow the reaction (about 5h of reaction), cool, precipitate the solid, filter, and recrystallize the solid with methanol / water, Compound 1 was obtained with a yield of 53%.

[0080] Compound 1 1 H NMR measurement result and mass spectrometry...

Embodiment 2

[0081]Example 2: Preparation of N-n-butyl-4-thiomorpholino-1,8-naphthalimide (compound 2)

[0082]

[0083] (1) Synthesis of Intermediate A2

[0084] Take 1.39g (5mmol) 4-bromo-1,8-naphthalic anhydride, 0.557g (5.5mmol) thiomorpholine, 0.556g (5.5mmol) triethylamine respectively, add 15mL DMF, react at 85°C for 6h, cool After reaching room temperature, pour it into 150mL water and filter it with suction. The resulting solid was recrystallized from petroleum ether / ethyl acetate to obtain intermediate A2 (4-(4-bromophenylmercapto)-1,8-naphthalic anhydride) as a yellow solid with a yield of 75%.

[0085] (2) Synthesis of Compound 2

[0086] Take 299mg (1mmol) of intermediate A2, 365mg (5mmol) of n-butylamine and 506mg (5mmol) of triethylamine respectively, add 10mL of ethanol, reflux under the protection of nitrogen, spot the plate to track the reaction (about 5h of reaction), cool down, and precipitate the solid. After filtration, the solid was recrystallized from methanol...

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Abstract

The invention provides a 4-substituted naphthalimide compound and a use thereof. The compound has a structure shown in the general formula I. The compound can competitively bind and antagonize with Bcl-2 and Mcl-1 proteins in vitro and in cells so that apoptosis is induced and thus the compound is a high activity apoptosis inducing agent and an antitumor compound. The derivative based on the compound can be used as a bifunctional molecule for external and intracellular recognition, separation, enrichment and fluorescence detection of Bcl-2 family proteins or can be used as a PROTAC bifunctional complex for intracellular selective degradation of Bcl-2 and Mcl-1 proteins so that the level of the Bcl-2 family proteins in living cells can be adjusted and controlled.

Description

technical field [0001] The invention relates to a class of 4-substituted naphthalimide compounds, in particular to 4-thiomorpholino-1,8-naphthalimides and derivatives thereof. It specifically relates to the competitive binding and antagonism of Bcl-2 and Mcl-1 proteins of these compounds in vitro and in vivo, thereby inducing cell apoptosis and application as anticancer compounds; some of the derivatives are used as activity-based molecular probes in vitro and the application of intracellular recognition, separation, enrichment and fluorescence detection of Bcl-2 family proteins; and some of these compounds act as PROTAC (Proteolysis Targeting Chimera) bifunctional complexes to selectively degrade Bcl-2 and Mcl-1 proteins in cells application. Background technique [0002] The Bcl-2 family protein (B-cell lymphoma 2 family of proteins) is the vertex and core factor of the endogenous pathway of mitochondrial apoptosis, and is a key family protein that regulates apoptosis. I...

Claims

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Application Information

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IPC IPC(8): C07D221/14C07D401/12C07D401/04C07D417/14C07D401/14C07K5/062A61K31/541A61K31/473A61K38/05A61P35/00G01N33/533G01N33/559
Inventor 张志超王紫千
Owner DALIAN UNIV OF TECH
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