1. Inhibition of thioredoxin reductase by a novel series of bis-1,2-benzisoselenazol-3(2H)-ones: Organoselenium compounds for cancer therapy
- Author
-
He, Jie, Li, Dongdong, Xiong, Kun, Ge, Yongjie, Jin, Hongwei, Zhang, Guozhou, Hong, Mengshi, Tian, Yongliang, Yin, Jin, and Zeng, Huihui
- Subjects
- *
THIOREDOXIN reductase (NADPH) , *ORGANOSELENIUM compounds , *CANCER treatment , *THIOREDOXIN , *GLUTATHIONE reductase , *APOPTOSIS , *METASTASIS , *ENZYME inhibitors - Abstract
Abstract: 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′-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. [Copyright &y& Elsevier]
- Published
- 2012
- Full Text
- View/download PDF