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High-specificity fluorescent probe for human carboxylesterase hCE2 and application thereof

A high-specificity, fluorescent probe technology, applied in the field of medicine, to achieve high selectivity, fast and efficient evaluation of enzyme activity and inhibitory activity, and easy detection of metabolites

Active Publication Date: 2015-05-06
CHANGSHU RES INST OF DALIAN UNIV OF TECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In addition, some intravenously administered prodrugs, such as irinotecan hydrochloride, are excreted into the intestine through biliary excretion, and then hydrolyzed by hCE2 in the intestine to release the toxic metabolite SN-38, which is considered to be The main cause of delayed diarrhea side effect of irinotecan

Method used

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  • High-specificity fluorescent probe for human carboxylesterase hCE2 and application thereof
  • High-specificity fluorescent probe for human carboxylesterase hCE2 and application thereof
  • High-specificity fluorescent probe for human carboxylesterase hCE2 and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0029] Embodiment 1 The chemical synthesis of 4-trifluoromethyl-7-hydroxycoumarin 4-ethylbenzoyl ester

[0030] (1) To 10 mL of tetrahydrofuran solution containing 0.5 mmol of 4-trifluoromethyl-7-hydroxycoumarin and 0.625 mmol of triethylamine, slowly drop 0.6 mmol of p-ethylbenzoyl chloride (dissolved in 5 mL of in tetrahydrofuran), the temperature is controlled at 0°C;

[0031] (2) After stirring in an ice bath for 1 h, the solution was returned to room temperature and stirred overnight;

[0032] (3) The solvent was removed from the reaction solution under reduced pressure, and the residual solid was purified by silica gel chromatography, and eluted with ethyl acetate-n-hexane (1:3 v / v), to obtain 135 mg of pure white solid powder. 1 H NMR (400MHz, CDCl 3 )δ8.23–8.18(m,2H), 7.80(dt,J=8.8,1.8Hz,1H), 7.69(ddd,J=7.0,4.1,1.3Hz,1H), 7.59–7.49(m,2H) , 7.37 (d, J=2.3Hz, 1H), 7.29 (dd, J=8.8, 2.3Hz, 1H), 6.80 (s, 1H).

Embodiment 2

[0033] Example 2 The chemical synthesis of 4-trifluoromethyl-7-hydroxycoumarin 4-chlorobenzoyl ester

[0034] (1) To 10 mL of tetrahydrofuran solution containing 0.5 mmol of 4-trifluoromethyl-7-hydroxycoumarin and 0.625 mmol of triethylamine, slowly add 0.6 mmol of p-chlorobenzoyl chloride (dissolved in 5 mL of tetrahydrofuran In), the temperature is controlled at 0°C;

[0035] (2) After stirring in an ice bath for 1 h, the solution was returned to room temperature and stirred overnight;

[0036] (3) The solvent was removed from the reaction solution under reduced pressure, and the residual solid was purified by silica gel chromatography, and eluted with ethyl acetate-n-hexane (1:3 v / v), to obtain 132 mg of pure white solid powder.

Embodiment 3

[0037] Example 3 The chemical synthesis of 4-trifluoromethyl-7-hydroxycoumarin 4-methylbenzoyl ester

[0038] (1) To 10 mL of tetrahydrofuran solution containing 0.5 mmol of 4-trifluoromethyl-7-hydroxycoumarin and 0.625 mmol of triethylamine, slowly drop 0.6 mmol of p-toluyl chloride (dissolved in 5 mL of in tetrahydrofuran), the temperature is controlled at 0°C;

[0039] (2) After stirring in an ice bath for 1 h, the solution was returned to room temperature and stirred overnight;

[0040] (3) The solvent was removed from the reaction solution under reduced pressure, and the residual solid was purified by silica gel chromatography, and eluted with ethyl acetate-n-hexane (1:3 v / v), to obtain 131 mg of pure white solid powder.

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Abstract

The invention discloses a high-specificity fluorescent probe for human carboxylesterase hCE2 and an application thereof. The substrate of the specific probe is an ester derivative of a 4-trifluoromethyl-7-umbelliferone compound and can be used for detection for the existence of hCE2 in different biological samples and quantitative determination for the vitality of hCE2. A specific flow for determining the enzymatic activity is as follows: selecting a hydrolysis reaction of the 4-trifluoromethyl-7-umbelliferone ester derivative as a probe reaction, selecting a proper substrate concentration, and determining the actual activity of the hCE2 enzyme in various biological samples, cells, carriers and overall organs by quantitatively detecting the generation amount of a hydrolysis metabolite 4-trifluoromethyl-7-umbelliferone in a unit time within a linear reaction interval. The high-specificity fluorescent probe disclosed by the invention can be used for quantitative evaluation for the activity of the hCE2 enzyme in biological samples from different sources; in addition, the probe reaction can also be used for rapidly screening an hCE2 inhibitor in vitro.

Description

technical field [0001] The invention belongs to the technical field of medicine, and in particular relates to a specific fluorescent probe of human carboxylesterase subtype 2 (hES2) and an application thereof. Background technique [0002] Carboxylesterase (CES) is an important phase I hydrolysis metabolic enzyme in the body, which catalyzes the ester bond breakage of various endogenous and exogenous compounds, releasing polar alcohol and carboxylic acid molecular fragments, which in turn It is continuously catalyzed and metabolized by other metabolic enzymes such as CYP450 or UGTs in the body, so that drug molecules can be excreted more effectively. A variety of drug molecules containing ester bonds in their structures, such as irinotecan hydrochloride (irinotecan, CPT-11), oseltamivir (Tamiflu), clopidogrel, etc., are catalyzed by carboxylesterase for activation or metabolic elimination. [0003] The carboxylesterases that mediate drug metabolism in the human body are mai...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C09K11/06C12Q1/44C12Q1/04C07D311/16C07D409/12C07D407/12
Inventor 崔京南冯磊
Owner CHANGSHU RES INST OF DALIAN UNIV OF TECH CO LTD
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