Synthesis and biological evaluation of disulfides as anticancer agents with thioredoxin inhibition

[Display omitted] •A convenient assay for screening thioredoxin (Trx) inhibitors has been established.•Compound 68 displays higher cytotoxicity than the known Trx inhibitor PX-12.•Compound 68 promotes apoptosis of cancer cells involving Trx inhibition. Altered redox homeostasis as a hallmark of canc...

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Bibliographic Details
Published in:Bioorganic chemistry 2021-05, Vol.110, p.104814-104814, Article 104814
Main Authors: Wei, Xiangxu, Zhong, Miao, Wang, Song, Li, Lexun, Song, Zi-Long, Zhang, Junmin, Xu, Jianqiang, Fang, Jianguo
Format: Article
Language:English
Subjects:
Anticancer
Apoptosis
Disulfide
Oxidative stress
Thioredoxin
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Summary:[Display omitted] •A convenient assay for screening thioredoxin (Trx) inhibitors has been established.•Compound 68 displays higher cytotoxicity than the known Trx inhibitor PX-12.•Compound 68 promotes apoptosis of cancer cells involving Trx inhibition. Altered redox homeostasis as a hallmark of cancer cells is exploited by cancer cells for growth and survival. The thioredoxin (Trx), an important regulator in maintaining the intracellular redox homeostasis, is cumulatively recognized as a promising target for the development of anticancer drugs. Herein, we synthesized 72 disulfides and evaluated theirinhibition for Trx and antitumor activity. First, we established an efficient and fast method to screen Trx inhibitors by using the probe NBL-SS that was developed by our group to detect Trx function in living cells. After an initial screening of the Trx inhibitory activity of these compounds, 8 compounds showed significant inhibition activity against Trx. We then evaluated the cytotoxicity of these 8 disulfides, compounds 68 and 69 displayed high cytotoxicity to HeLa cells, but less sensitive to normal cell lines. Next, we performed kinetic studies of both two disulfides, 68 had faster inhibition of Trx than 69. Further studies revealed that 68 led to the accumulation of reactive oxygen species and eventually induced apoptosis of Hela cells via inhibiting Trx. The establishment of a method for screening Trx inhibitors and the discovery of 68 with remarkable Trx inhibition provide support for the development of anticancer candidates with Trx inhibition.
ISSN:0045-2068
1090-2120
DOI:10.1016/j.bioorg.2021.104814