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High-specificity fluorescent probe of human carboxylesterase CES2 and application thereof

A high-specificity, fluorescent probe technology, applied in the field of high-specificity fluorescent probes, to achieve the effect of simple synthesis process

Active Publication Date: 2015-05-27
ZHANGJIAGANG IND TECH RES INST CO LTD DALIAN INST OF CHEM PHYSICS CHINESE ACADEMY OF SCI +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

In addition, some intravenously administered prodrugs, such as irinotecan hydrochloride, will be excreted into the intestine through biliary excretion, and then hydrolyzed by CES2 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 of human carboxylesterase CES2 and application thereof
  • High-specificity fluorescent probe of human carboxylesterase CES2 and application thereof
  • High-specificity fluorescent probe of human carboxylesterase CES2 and application thereof

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Experimental program
Comparison scheme
Effect test

Embodiment 13

[0044] The chemical synthesis of embodiment 13-hydroxyflavone 4-ethylbenzoyl ester

[0045] (1) Slowly add 0.6 mmol of p-ethylbenzoyl chloride (dissolved in 5 mL of tetrahydrofuran) dropwise to 10 mL of tetrahydrofuran solution containing 0.5 mmol of 3-hydroxyflavone and 0.625 mmol of triethylamine, and control the temperature at 0°C ;

[0046] (2) After stirring in an ice bath for 1 hour, the solution was brought to room temperature and stirred overnight;

[0047] (3) The solvent was removed from the reaction solution under reduced pressure, and the residual solid was purified by silica gel chromatography, eluting with ethyl acetate-n-hexane (1:3 v / v), to obtain 155 mg of pure white solid powder. δ( 1 H-NMR, 400MHz, CDCl 3 ):8.29(1H,dd),8.15-8.09(2H,m),7.98-7.90(2H,m),7.73(1H,ddd),7.59(1H,dd),7.50-7.42(4H,m), 7.32(2H,d), 2.74(2H,q), 1.35-1.22(3H,m). (See the synthetic route diagram figure 2 ) (see the hydrogen spectrum image 3 ).

Embodiment 23

[0048] The chemical synthesis of embodiment 23-hydroxyflavone 4-chlorobenzoyl ester

[0049] (1) Slowly add 0.6 mmol of p-chlorobenzoyl chloride (dissolved in 5 mL of tetrahydrofuran) dropwise to 10 mL of tetrahydrofuran solution containing 0.5 mmol of 3-hydroxyflavone and 0.625 mmol of triethylamine, and control the temperature at 0°C;

[0050] (2) After stirring in an ice bath for 1 hour, the solution was brought to room temperature and stirred overnight;

[0051] (3) The solvent was removed from the reaction solution under reduced pressure, and the residual solid was purified by silica gel chromatography, eluting with ethyl acetate-n-hexane (1:3 v / v), to obtain 152 mg of pure white solid powder. δ( 1 H-NMR, 400MHz, CDCl 3 ):8.29(1H,dd),8.13(2H,m),7.92-.89(2H,m),7.77-7.72(1H,ddd),7.60(1H,dd),7.49-7.46(6H,m) . (Synthetic route map see figure 2 ) (see the hydrogen spectrum Figure 4 ).

Embodiment 33

[0052] The chemical synthesis of embodiment 33-hydroxyflavone 4-methylbenzoyl ester

[0053] (1) Slowly add 0.6 mmol of p-toluoyl chloride (dissolved in 5 mL of tetrahydrofuran) dropwise to 10 mL of tetrahydrofuran solution containing 0.5 mmol of 3-hydroxyflavone and 0.625 mmol of triethylamine, and control the temperature at 0°C ;

[0054] (2) After stirring in an ice bath for 1 hour, the solution was brought to room temperature and stirred overnight;

[0055] (3) The solvent was removed from the reaction solution under reduced pressure, and the residual solid was purified by silica gel chromatography, eluting with ethyl acetate-n-hexane (1:3 v / v), to obtain 151 mg of pure white solid powder. δ( 1 H-NMR, 400MHz, CDCl 3 ):8.30(1H,dd),8.10-8.12(2H,m),7.96-7.94(2H,m),7.75(1H,ddd),7.61(1H,dd),7.50-7.44(4H,m), 7.31(2H,d), 2.46(2H,s). (See the synthetic route diagram figure 2 ) (see the hydrogen spectrum Figure 5 ).

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Abstract

A high-specificity fluorescent probe of human carboxylesterase CES2 and an application thereof. A substrate of the high-specificity fluorescent probe is an ester derivative of a 3-hydroxyl flavonoid compound, which can be used for detecting the existence of the CES2 in different bio-samples and quantitatively measuring the activity of the CES2. A particular measurement process of the enzyme activity includes following steps: selecting a hydrolysis reaction of the derivative of the 3-hydroxyl flavonoid compound as a probe reaction; selecting generation amount of a hydrolytic metabolite, 3-hydroxyl flavonoid, in unit time through quantitative detection with selection of a proper substrate concentration in a linear reaction section so that the actual activity of the CES2 enzyme in various bio-samples, cells, in-vivo organs and overall organs can be measured. The high-specificity fluorescent probe not only can be used for quantitative evaluation of the enzyme activity of the CES2 in the bio-samples from different sources, but also can be used for in-vitro quickly screening an inhibitor of the CES2 by means of the probe reaction.

Description

technical field [0001] The invention belongs to the technical field of medicine, and in particular relates to a highly specific fluorescent probe of human carboxylesterase CES2 (Carboxylesterase 2) and an application thereof. Background technique [0002] Carboxylesterase (CES) is an important one-phase hydrolytic 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 ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C09K11/06C07D311/30C12Q1/44G01N21/64C12Q1/04
Inventor 杨凌冯磊崔京南葛广波刘兆明
Owner ZHANGJIAGANG IND TECH RES INST CO LTD DALIAN INST OF CHEM PHYSICS CHINESE ACADEMY OF SCI
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