Format

Send to

Choose Destination
Eur J Med Chem. 2018 Jan 1;143:1090-1102. doi: 10.1016/j.ejmech.2017.05.022. Epub 2017 May 6.

Organic arsenicals target thioredoxin reductase followed by oxidative stress and mitochondrial dysfunction resulting in apoptosis.

Author information

1
State Key Laboratory of Virology, Key Laboratory of Analytical Chemistry for Biology and Medicine (MOE), College of Chemistry and Molecular Sciences, Wuhan University, Wuhan 430072, PR China.
2
Collaborative Innovation Center of Chemistry for Life Sciences, School of Life Sciences, University of Sciences and Technology of China, Hefei 230027, PR China.
3
College of Chemistry and Chemical Engineering, Hubei Normal University, Huangshi 435002, PR China.
4
State Key Laboratory of Virology, Key Laboratory of Analytical Chemistry for Biology and Medicine (MOE), College of Chemistry and Molecular Sciences, Wuhan University, Wuhan 430072, PR China; College of Chemistry and Chemical Engineering, Hubei Normal University, Huangshi 435002, PR China; College of Chemistry and Chemical Engineering, Wuhan University of Science and Technology, Wuhan 430081, PR China. Electronic address: yiliuchem@whu.edu.cn.
5
Collaborative Innovation Center of Chemistry for Life Sciences, School of Life Sciences, University of Sciences and Technology of China, Hefei 230027, PR China. Electronic address: geyushu@ustc.edu.cn.

Abstract

Considering the vital role of cellular redox state, more and more researches focus on the design of drugs targeting thioredoxin reductase (TrxR), an important enzyme in maintaining the balance of cellular redox. Here two organic arsenicals, 2-(((4-(1,3,2-dithiarsinan-2-yl) phenyl) imino) methyl) phenol (PIM-PAO-PDT) and N-(4-(1,3,2-dithiarsinan-2-yl) phenyl)-2-hydroxybenzamide (PAM-PAO-PDT), bearing the S-As-S chemical scaffold and different linking groups have been synthesized, and both of them show the better inhibitory activity and selectivity towards HL-60 cells. Importantly, it is illustrated that they can target TrxR selectively and inhibit its activity via the disturbance for Cys83 and Cys88 located in conserved active sites. Afterwards, the cells suffer from the burst of ROS, consumption of antioxidants and high sensitivity for oxidants, which further damage the mitochondria leading to dysfunction including the collapse of membrane potential, ATP level decline, mitochondrial membrane swelling, MPTP opening, Ca2+ and cytochrome c release. Then the mitochondria-dependent apoptosis is triggered by PIM-PAO-PDT and PAM-PAO-PDT, which can also be deterred in the presence of NAC, DTT or LA. Although the organic arsenicals can suppress TrxR activity, the following oxidative stress and mitochondrial dysfunction are the main causes for apoptosis.

KEYWORDS:

Mitochondrial dysfunction; Organic arsenicals; Oxidative stress; TrxR

PMID:
29150332
DOI:
10.1016/j.ejmech.2017.05.022
[Indexed for MEDLINE]

Supplemental Content

Full text links

Icon for Elsevier Science
Loading ...
Support Center