Inhibition of thioredoxin reductase by a novel series of bis-1,2-benzisoselenazol-3(2H)-ones: Organoselenium compounds for cancer therapy

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• 作者：Jie He^a ; ^b ; ^&dagger ; ; Dongdong Li^c ; ^&dagger ; ; Kun Xiong^a ; ^b ; Yongjie Ge^a ; ^b ; Hongwei Jin^a ; Guozhou Zhang^a ; ^b ; Mengshi Hong^a ; ^b ; Yongliang Tian^a ; ^b ; Jin Yin^a ; ^b ; Huihui Zeng^a ; ^b ; ^c ; ^{zenghh@bjmu.edu.cn}
• 关键词：TrxR ; thioredoxin reductase ; Trx ; thioredoxin ; GR ; glutathione reductase ; SAR ; structure&ndash ; activity relationship ; DTNB ; 5 ; 5&prime ; -dithiol-bis-2-nitrobenzoic acid ; Log  ; Pcal ; calculated Log  ; P ; BIAM ; biotin-conjugated iodoacetamide
• 刊名：Bioorganic and Medicinal Chemistry
• 出版年：2012
• 期刊代码：9_09680896
• 类别：ch
• 出版时间：15 June, 2012
• 卷：20
• 期：12
• 页码：3816-3827
• 文件大小：947 K

摘要

Thioredoxin reductase (TrxR) is critical for cellular redox regulation and is involved in tumor proliferation, apoptosis and metastasis. Its C-terminal redox-active center contains a cysteine (Cys497) and a unique selenocysteine (Sec498), which are exposed to solvent and easily accessible. Thus, it is becoming an important target for anticancer drugs. Selective inhibition of TrxR by 1,2-(bis-1,2-benzisoselenazol-3(2H)-one)ethane (4a) prevents proliferation of several cancer cell lines both in vivo and in vitro. Using the structure of 4a as a starting point, a series of novel bis-1,2-benzisoselenazol-3(2H)-ones was designed, prepared and tested to explore the structure-activity relationships (SARs) for this class of inhibitor and to improve their potency. Notably, 1,2-(5,5鈥?dimethoxybis(1,2-benzisoselenazol-3(2H)-one))ethane (12) was found to be more potent than 4a in both in vitro and in vivo evaluation. Its binding sites were confirmed by biotin-conjugated iodoacetamide assay and a SAR model was generated to guide further structural modification.