Graduate School of Science, Nagoya University, Furo-cho, Chikusa-Ku, Nagoya, Aichi, 464-8602, Japan.
Faculty of Pharmaceutical Science, Hokkaido University, Kita-12, Nishi-6, Kita-Ku, Sapporo, Hokkaido, 060-0812, Japan.
Chembiochem. 2019 Apr 1;20(7):900-905. doi: 10.1002/cbic.201800671. Epub 2019 Feb 15.
Glutathione S-transferase π (GSTP ) is overexpressed in many types of cancer and is involved in drug resistance. Therefore, GSTP 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 GSTP both in vitro and in cellulo with a long duration of action.
谷胱甘肽 S-转移酶 π（GSTP）在许多类型的癌症中过度表达，并与耐药性有关。因此，GSTP 是癌症治疗的一个重要靶点，已经报道了许多 GST 抑制剂。我们之前开发了一种不可逆抑制剂 GS-ESF，作为一种有效的 GST 抑制剂；然而，其细胞通透性太低，无法用于抑制细胞内 GST。我们现在通过在氯硝基苯（CNB）中引入磺酰氟（SF）开发了新的不可逆抑制剂。作用机制被揭示为 CNBSF 首先通过细胞中的芳香取代与谷胱甘肽（GSH）反应，然后 GSH 上的磺酰基与 CNBSF 上的磺酰基反应，与 GST 的 Tyr108 形成磺酰酯键。我们的新型抑制剂对 GSTP 的体外和细胞内抑制作用均具有不可逆性和长效性。
