Azole Ketone Benzene And Different Selenium Thioredoxin Reductase Inhibitors Of The Design, Synthesis, Evaluation Of Activity And Structure-activity Relationship Study

Thioredoxin reductase (TrxR) is critical for cellular redox regulation and isinvolved in tumor proliferation, apoptosis and metastasis. Its C-terminal redox-activecenter contains a cysteine (Cys497) and a unique selenocysteine (Sec498), which areexposed to solvent and easily accessible. Thus, it is becoming an important target foranticancer drugs. 1,2-(bis-1,2-benzisoselenazol-3(2H)-one)ethane (4a), also calledethaselen, was prepared by our group previously. The selective inhibition of TrxR by4a could prevent proliferation of several cancer cell lines both in vivo and in vitro.Here, using the structure of 4a as a starting point, a series of novelbis-1,2-benzisoselenazol-3(2H)-ones was designed, prepared and tested to explore thestructure-activity relationships (SARs) for this class of TrxR inhibitors and to identifynew compounds with improved potency as anticancer drugs. Notably,1,2-(5,5’-dimethoxybis(1,2-benzisoselenazol-3(2H)-one))ethane (12) was found to bemore potent than 4a in both in vitro and in vivo tests. Its binding sites were confirmedby biotin-conjugated iodoacetamide (BIAM) assay and a SAR model was generatedto guide further structural modification.