Structure-activity relationship studies of phenothiazine derivatives as a new class of ferroptosis inhibitors together with the therapeutic effect in an ischemic stroke model

被引:64
作者
Yang, Wei [1 ]
Liu, Xiaolong [1 ,3 ]
Song, Chunli [2 ]
Ji, Sen [1 ]
Yang, Jianhong [2 ]
Liu, Yang [1 ]
You, Jing [1 ]
Zhang, Jie [1 ]
Huang, Shenzhen [1 ]
Cheng, Wei [1 ]
Shao, Zhenhua [1 ]
Li, Linli [2 ]
Yang, Shengyong [1 ]
机构
[1] Sichuan Univ, West China Hosp, State Key Lab, Biotherapy & Canc Ctr, Chengdu 610041, Sichuan, Peoples R China
[2] Sichuan Univ, West China Sch Pharm, Key Lab Drug Targeting & Drug Delivery Syst, Educ Minist, Chengdu 610041, Sichuan, Peoples R China
[3] Yanan Univ, Coll Med, Yanan 716000, Shanxi, Peoples R China
基金
中国国家自然科学基金;
关键词
Ferroptosis inhibitor; Structure-activity relationship; Ischemic stroke; Promethazine derivatives; CEREBRAL-ARTERY OCCLUSION; NONAPOPTOTIC CELL-DEATH; MECHANISMS; APOPTOSIS; DAMAGE; FORM; NEUROPROTECTION; NECROPTOSIS; REPERFUSION; PYROPTOSIS;
D O I
10.1016/j.ejmech.2020.112842
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
Ferroptosis is a new type of programmed cell death discovered recently and has been demonstrated to be involved in a number of human diseases such as ischemic stroke. Ferroptosis inhibitors are expected to have potential to treat these diseases. Herein, we report the identification of promethazine derivatives as a new type of ferroptosis inhibitors. Structure-activity relationship (SAR) analyses led to the discovery of the most potent compound 2-(1-(4-(4-methylpiperazin-1-yl)phenyl)ethyl)-10H-phenothiazine (51), which showed an EC50 (half maximal effective concentration) value of 0.0005 mu M in the erastin-induced HT1080 cell ferroptosis model. In the MCAO (middle cerebral artery occlusion) ischemic stroke model, 51 presented an excellent therapeutic effect. This compound also displayed favorable pharmacokinetic properties, in particular, a good ability to permeate the blood-brain barrier. Overall, 51 could be a promising lead compound for the treatment of ferroptosis related diseases and deserves further investigations. (c) 2020 Elsevier Masson SAS. All rights reserved.
引用
收藏
页数:21
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