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.
References
Dec 21, 1982·Biochemistry·M Luthman, A Holmgren
Aug 12, 2003·Proteins·Marcel L VerdonkRichard D Taylor
May 14, 2005·Antioxidants & Redox Signaling·Hajime Nakamura
Sep 16, 2006·Chembiochem : a European Journal of Chemical Biology·Stephan GromerWolfgang Brandt
Nov 23, 2006·Antioxidants & Redox Signaling·Christopher Horst Lillig, Arne Holmgren
Apr 15, 2009·Biochimica Et Biophysica Acta·Elias S J Arnér
Sep 25, 2010·Differentiation; Research in Biological Diversity·Hanwei YinHuihui Zeng
May 13, 2011·Anti-cancer Drugs·Lei WangHui-Hui Zeng
Jan 3, 2012·Free Radical Biology & Medicine·Lihui WangHuihui Zeng
Citations
Mar 18, 2015·Journal of Enzyme Inhibition and Medicinal Chemistry·Wei ChenXiangming Guan
Nov 28, 2015·Journal of Medicinal Chemistry·Luca SancinetoOriana Tabarrini
Mar 31, 2015·European Journal of Medicinal Chemistry·Jun YanXingshu Li
Jul 12, 2016·Pharmaceuticals·Jim KüppersMichael Gütschow
Dec 6, 2016·Acta Pharmacologica Sinica·Suo-Fu YeWei Lu
Jun 13, 2017·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Mirosław GiurgMagdalena Piętka-Ottlik
Apr 26, 2016·Dalton Transactions : an International Journal of Inorganic Chemistry·Yuan-Yuan ZhangChun-Lin Ma
Apr 30, 2019·International Journal of Molecular Sciences·Izabella JastrzebskaClaudio Santi
Aug 1, 2013·The Journal of Biological Chemistry·Jun LuArne Holmgren
Oct 3, 2014·Chemical & Pharmaceutical Bulletin·Yikai ZhangXueyun Zhong
Jun 2, 2015·Chemical & Pharmaceutical Bulletin·Fen JingBaoquan Chen
Dec 24, 2019·Essays in Biochemistry·Elias S J Arnér
Dec 19, 2012·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Jun LuArne Holmgren
Jul 4, 2020·Journal of Biochemical and Molecular Toxicology·Guanghui RenMohd Islahuddin Mohd Tamrin
Nov 16, 2016·Scientific Reports·Chaoran DongHuihui Zeng
Sep 5, 2018·Journal of Zhejiang University. Science. B·Qiao ZouHui-Hui Zeng
May 5, 2018·Medicinal Research Reviews·Junmin ZhangJianguo Fang
Nov 11, 2020·Chembiochem : a European Journal of Chemical Biology·Jennie O'LoughlinMarina Rubini
Aug 11, 2019·European Journal of Medicinal Chemistry·Mirna JovanovićMikhail Krasavin
Oct 2, 2017·Redox Biology·Xiaoqing ZhengHuihui Zeng
May 22, 2021·Molecular Informatics·Pablo Andrei NogaraJoão Batista Teixeira Rocha
Feb 18, 2017·Analytical Chemistry·Min ZhuBenfang Helen Ruan
Dec 14, 2018·Journal of Medicinal Chemistry·Zhao ChenBenfang Helen Ruan
Sep 21, 2021·Frontiers in Molecular Biosciences·Wenxuan JiaoJinhua Wen
Oct 29, 2021·Chemistry : a European Journal·Qing-Feng Xu-XuMasahiro Miura