A Covalent Inhibitor for Glutathione S-Transferase Pi (GSTP1-1 ) in Human Cells.,ChemBioChem

当前位置： X-MOL 学术 › ChemBioChem › 论文详情

Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)

A Covalent Inhibitor for Glutathione S-Transferase Pi (GSTP1-1 ) in Human Cells.
ChemBioChem ( IF 2.6 ) Pub Date : 2019-02-15 , DOI: 10.1002/cbic.201800671
Yuko Shishido _{1,

2} , Fumiaki Tomoike ₃ , Keiko Kuwata ₄ , Haruka Fujikawa ₁ , Yoshitaka Sekido ₅ , Yuko Murakami-Tonami _{5,

6} , Tomoshi Kameda ₇ , Naoko Abe ₁ , Yasuaki Kimura ₁ , Satoshi Shuto ₂ , Hiroshi Abe ₁

Affiliation

Glutathione S-transferase π (GSTP1-1 ) is overexpressed in many types of cancer and is involved in drug resistance. Therefore, GSTP1-1 is an important target in cancer therapy, and many GST inhibitors have been reported. We had previously developed an irreversible inhibitor, GS-ESF, as an effective GST inhibitor; however, its cellular permeability was too low for it to be used in inhibiting intracellular GST. We have now developed new irreversible inhibitors by introducing sulfonyl fluoride (SF) into chloronitrobenzene (CNB). The mechanism of action was revealed to be that CNBSF first reacts with glutathione (GSH) through an aromatic substitution in the cell, then the sulfonyl group on the GSH conjugate with CNBSF reacts with Tyr108 of GST to form a sulfonyl ester bond. Our new inhibitor irreversible inhibited GSTP1-1 both in vitro and in cellulo with a long duration of action.

中文翻译：

人体细胞中谷胱甘肽S-转移酶Pi（GSTP1-1）的共价抑制剂。

谷胱甘肽S转移酶π（GSTP1-1）在许多类型的癌症中均过表达，并且与药物抗性有关。因此，GSTP1-1是癌症治疗中的重要靶标，并且已经报道了许多GST抑制剂。我们之前已经开发出一种不可逆的抑制剂GS-ESF作为有效的GST抑制剂。然而，它的细胞通透性太低，不能用于抑制细胞内GST。现在，我们通过将磺酰氟（SF）引入氯硝基苯（CNB）中来开发新的不可逆抑制剂。揭示了其作用机理是CNBSF首先通过细胞中的芳族取代与谷胱甘肽（GSH）反应，然后与CNBSF结合的GSH缀合物上的磺酰基与GST的Tyr108反应形成磺酰基酯键。

更新日期：2019-02-15

点击分享查看原文

点击收藏

阅读更多本刊新发论文本刊介绍/投稿指南