Thio/oxo-naphthalimide compound and application thereof

A technology of oxynaphthoimides and compounds, which is applied in the field of 4-phenylmercapto-1,8-naphthoimides and its derivatives, and can solve the problems of insufficient similarity, apoptosis, and unsatisfactory effects, etc. question

Inactive Publication Date: 2017-11-24
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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  • Thio/oxo-naphthalimide compound and application thereof
  • Thio/oxo-naphthalimide compound and application thereof
  • Thio/oxo-naphthalimide compound and application thereof

Examples

Experimental program
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Effect test

preparation example Construction

[0046] The present invention further provides the preparation method of the above-mentioned sulfur / oxynaphthimide compounds of the present invention, comprising the steps of:

[0047] (1) 4-bromo-naphthalene dicarboxylic anhydride and R 1 XH 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; The steps are preferably carried out under nitrogen protection;

[0048]

[0049] (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 ) to replace 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 ...

Embodiment 1

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

[0075]

[0076] (1) Synthesis of Intermediate A1

[0077] Take 1.39g (5mmol) 4-bromo-1,8-naphthalic anhydride, 0.682g (5.5mmol) p-cresol, 0.556g triethylamine respectively, add 15mL DMF, react at 85°C for 6h, cool to room temperature Pour into 150mL of water and filter with suction. The resulting solid was recrystallized from petroleum ether / ethyl acetate to obtain intermediate A1 (4-(4-methylphenylmercapto)-1,8-naphthalic anhydride) as a yellow solid with a yield of 78%.

[0078] (2) Synthesis of Compound 1

[0079] Take 320mg 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 N...

Embodiment 2

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

[0082]

[0083] (1) Synthesis of Intermediate A2

[0084] Take 1.39g (5mmol) 4-bromo-1,8-naphthalic anhydride, 0.940g (5.5mmol) p-bromothiophenol, 0.556g (5.5mmol) triethylamine respectively, add 15mL DMF, and react at 85°C for 6h , cooled to room temperature, poured into 150mL water, and filtered 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 384mg (1mmol) of intermediate A2, 365mg (5mmol) of n-butylamine and 506mg (5mmol) of triethylamine, add 10mL of ethanol, reflux under the protection of nitrogen, spot the plate to follow the reaction (about 5h of reaction), cool down, and precipitate the solid. After filtration, the solid was recrystallized from methanol / wate...

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Abstract

The invention provides a thio / oxo-naphthalimide compound and application thereof. The compound has a structure shown as a general formula I. The compounds are capable of realizing competitive binding and antagonism of Bcl-2 and Mcl-1 proteins in vitro and in cells so as to induce cell apoptosis, and refer to a type of apoptosis inducers and antitumor compounds with extremely high activities. In addition, the derivative designed based on the compound can serve as a bifunctional molecule and is capable of recognizing, separating, enriching and realizing fluorescence detection of Bcl-2 family proteins; or the derivative can serve as a PROTAC bifunctional complex for selectively degrading the Bcl-2 and Mcl-1 proteins in the cells, so that the level of the Bcl-2 family proteins in living cells is regulated. The structural formula is as shown in the specification.

Description

technical field [0001] The invention relates to a class of sulfur / oxynaphthoimide compounds, in particular to 4-phenylmercapto-1,8-naphthoimides 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 apoptosis and application as anticancer compounds; some of these compounds are used as activity-based molecular probes in vitro and in vivo The application of intracellular recognition, separation, enrichment and fluorescence detection of Bcl-2 family proteins; and the application of some of these compounds as PROTAC (Proteolysis Targeting Chimera) bifunctional complexes to selectively degrade Bcl-2 and Mcl-1 proteins in cells . 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. ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D221/14C07D401/12C07D401/04C07D417/14C07D401/14C09K11/06A61P35/00G01N21/64G01N33/68G01N33/533
CPCC07D221/14C07D401/04C07D401/12C07D401/14C07D417/14C09K11/06C09K2211/1007C09K2211/1029C09K2211/1037C09K2211/1044G01N21/6428G01N33/533G01N33/68G01N2021/6439C09B57/08G01N2333/47
Inventor 张志超王紫千
Owner DALIAN UNIV OF TECH
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