Characterization of phenoxyacetic acid compounds in inhibition of human glutathione-S-transferase Mu

Bangtian XU; Dashu FANG; Yuqing XIE; Xiaolan YANG

doi:10.16016/j.2097-0927.202204145

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Characterization of phenoxyacetic acid compounds in inhibition of human glutathione-S-transferase Mu

Basic Medicine | 更新时间：2026-01-09

- Characterization of phenoxyacetic acid compounds in inhibition of human glutathione-S-transferase Mu
- Journal of Army Medical University Vol. 44, Issue 18, Pages: 1826-1834(2022)
- 作者机构：
  
  1.401331 重庆，重庆医科大学附属大学城医院药学部
  2.400016 重庆，重庆医科大学检验医学院，临床检验诊断学教育部重点实验室
- 作者简介：
- 基金信息：
  
  the General Program of National Natural Science Foundation of China(31570862);the Natural Science Foundation of Chongqing(cstc2019jcyj-msxmX0166);the Scientific Young Seedling Cultivation Project of the University-Town Hospital of Chongqing Medical University(2021JC03)
- DOI：10.16016/j.2097-0927.202204145
  CLC： R345;R914.4;R962
- Received：19 April 2022，
  
  Revised：2022-05-20，
  
  Published：30 September 2022
- 稿件说明：
移动端阅览
Bangtian XU, Dashu FANG, Yuqing XIE, et al. Characterization of phenoxyacetic acid compounds in inhibition of human glutathione-S-transferase Mu[J]. Journal of Army Medical University, 2022, 44(18): 1826-1834.
DOI：

Bangtian XU, Dashu FANG, Yuqing XIE, et al. Characterization of phenoxyacetic acid compounds in inhibition of human glutathione-S-transferase Mu[J]. Journal of Army Medical University, 2022, 44(18): 1826-1834. DOI： 10.16016/j.2097-0927.202204145.

摘要

目的

设计合成4个苯氧乙酸类化合物，通过不同方法表征其对人谷胱甘肽-S-转移酶Mu(glutathione-S-transferase Mu

GSTM)的抑制性能，考察苯氧乙酸类化合物与GSTM之间的构效关系。

方法

设计合成含α

β-不饱和酮结构的4-丙烯酰苯氧乙酰乙胺(Ⅰa)、N

N’-(4-(丙烯酰基)苯氧乙酰基)丁二胺(Ⅱa)和不含α

β-不饱和酮结构的4-丙酰苯氧乙酰乙胺(Ⅰb)、N

N’-(4-(丙酰基)苯氧乙酰基)丁二胺(Ⅱb)，利用初速度法表征4个化合物对GSTM的半抑制浓度(50% inhibiting concentration

)和表观抑制常数(inhibition constant

)，利用荧光光谱法表征4个化合物对GSTM的解离常数(dissociation constant

)。

结果

含α

β-不饱和酮结构的Ⅰa、Ⅱa可与谷胱甘肽(glutathione

GSH)发生亲电加成反应，与酶和GSH孵育原位生成产物后，其对GSTM的

分别为(67±6) μmol/L、(0.10±0.02) μmol/L (

=2)；不含α

β-不饱和酮结构的Ⅰb、Ⅱb对GSTM无明显抑制作用。Ⅰa相对GSH的

为(19.9±1.6) μmol/L，相对CDNB的

为(9.1±0.7) μmol/L (

=3)；Ⅱa相对GSH的

为(0.063±0.005) μmol/L，相对CDNB的

为(0.079±0.006) μmol/L (

=3)；可见Ⅱa较Ⅰa的

低(

0.05)。荧光光谱法测得Ⅰa、Ⅰb、Ⅱa、Ⅱb的

分别为(41.5±1.8) μmol/L、(38.9±1.7) μmol/L、(18.0±0.9) μmol/L、(19.5±1.0) μmol (

=2)；可见Ⅰa与Ⅰb、Ⅱa与Ⅱb之间的

无显著差异(

0.05)，而Ⅱa较Ⅰa、Ⅱb较Ⅰb的

低(

0.05)。

结论

β-不饱和酮结构是苯氧乙酸类化合物抑制作用的必须官能团；二价抑制剂Ⅱa、Ⅱb较单价抑制剂Ⅰa、Ⅰb对GSTM具有更高亲和力，Ⅱa的产物较Ⅰa的产物抑制作用更强。

Abstract

Objective

To design and synthesize 4 phenoxyacetic acid compounds

characterize their inhibitory potencies on human glutathione-S-transferase Mu (glutathione-S-transferase Mu

GSTM) by different methods

and investigate the structure-activity relationship between phenoxyacetic acid compounds and GSTM.

Methods

Four phenoxyacetic acid compounds were designed and synthesized

and they are ethyl 2-(4-acryloylphenoxy)acetate (Ⅰa) and N

N'-(butane-1

4-diyl)-bis-(4-acryloyl phenoxyacetic amide) (Ⅱa) containing α

β-unsaturated ketone structure

and ethyl 2-(4-propionylphenoxy)acetate (Ⅰb)

N'-(butane-1

4-diyl)-bis-(4-propionyl phenoxyacetic amide) (Ⅱb) not containing α

β-unsaturated ketone structure. They were characterized by the half-maximal inhibitory concentration (

) and apparent inhibition constant (

) using initial velocity method

and the dissociation constants (

) for GSTM utilizing fluorescence analysis.

Results

Ⅰa and Ⅱa contained α

β-unsaturated ketone structure that undergoes electrophilic addition reaction with GSH. After incubation with enzyme and GSH

Ⅰa and Ⅱa generated products in situ

with a

value of 67.00±6.00 and 0.10±0.02 μmol/L for GSTM respectively (

=2). Ⅰb and Ⅱb without α

β -unsaturated ketone structures had no inhibitory potencies for GSTM. The

of Ⅰa against GSH was 19.9±1.6

μmol/L

and the

against CDNB was 9.1±0.7 μmol/L (

=3). The

of Ⅱa against GSH was 0.063±0.005 μmol/L

and against CDNB was 0.079±0.006 μmol/L (

=3). The

of Ⅱa was lower than that ofⅠa (

0.05). The

of Ⅰa

Ⅰb

Ⅱa

and Ⅱb measured by fluorescence analysis were 41.5±1.8

38.9±1.7

18.0±0.9

and 19.5±1.0 μmol/L

respectively (

=2). The

between Ⅰa and Ⅰb

and between Ⅱa and Ⅱb had no significant differences(

0.05). The

of Ⅱa was lower than that of Ⅰa

and the

of Ⅱb was lower than that of Ⅰb (

0.05).

Conclusion

β-unsaturated ketone structure is the essential functional group of phenoxyacetic acid compounds for inhibition on GSTM. Comparing with monovalent Ⅰa and Ⅰb

divalent Ⅱa and Ⅱb have higher affinity for GSTM. The product of Ⅱa has inhibitory potency significantly higher than that of Ⅰa.

关键词

Keywords

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