Cyclodextrin-Derived Diorganyl Tellurides as Glutathione Peroxidase Mimics and Inhibitors of Thioredoxin Reductase and Cancer Cell Growth

Abstract

Water-soluble diorganyl tellurides of the alkyl aryl or dialkyl type were prepared by treatment of mono-6-tosyl-beta-cyclodextrin with sodium alkanetellurolates or arenetellurolates or sodium telluride. The novel cyclodextrin-derived organotelluriums were evaluated for their capacity to catalyze the reduction of hydrogen peroxide, tert-butyl hydroperoxide, and cumene hydroperoxide in the presence of glutathione, NADPH, and GSSG-reductase (coupled reductase assay). Cyclodextrins 4d and 4e, carrying 4-(N,N-dimethylamino)phenyltelluro and n-butyltelluro groups, respectively, were the most efficient glutathione peroxidase mimics. Reduction of lipophilic cumene hydroperoxide often proceeded 10-20 times faster than reduction of the more hydrophilic hydroperoxides, which cannot bind into the hydrophobic interior of the cyclodextrin. Thus, it seems that the carbohydrate moiety acts as a binding site for the hydroperoxide substrate. The cyclodextrin derivatives were also evaluated for their capacity to inhibit thioredoxin reductase/thioredoxin and cancer cell growth in culture. IC(50) values for inhibition of thioredoxin or thioredoxin/thioredoxin reductase were in the submicromolar range for the best inhibitors (compounds 4d and 5). Two of the compounds (4c and 5) were found to inhibit the growth of MCF-7 cells in culture with IC(50) values in the low micromolar range.

Differential genotoxicity of diphenyl diselenide (PhSe)2 and diphenyl ditelluride (PhTe)2

“…Tellurium (Te) has the potential of redox cycling which leads to formation of reactive oxygen species (ROS) which can damage biomolecules (Maciel et al,2000;Nogueira, Zeni & Rocha, 2004;Degrandi et al, 2010;Sailer et al, 2004;Caeran Bueno et al 2013). Organotellurium-induced intracellular ROS accumulation has been reported to be the cause of cell death in HL-60 and different types of cancer cells (McNaughton et al, 2004;Juan et al, 2010;Ding et al,2002;Rigobello et al, 2009). In contrast, exposure of mice to (PhSe)2 caused a significant decrease in the DNA damage index (DI) both after 48 and 96 hours of drug administration as shown in Table 1.…”

Catalytic application of selenium and tellurium compounds as glutathione peroxidase enzyme mimetics

“…Engman et al 21 have shown that the antioxidant capacity of telluride 35 is drastically increased when compared with their selenium congeners 20. 21 Later, in 2004, the same group described the synthesis and GPx like behavior of water soluble cyclodextrin derivatives containing tellurium, 36a-e. 32 Among organotellurides 36a-e, the cyclodextrin 36e carrying a butyltelluro group was the best catalyst. They also found that the catalytic efficiency of aryl derivatives decreased with decreasing electron density at tellurium (36d > 36c @ 36b > 36a).…”

Synthesis and Characterization of a New Five and Six Membered Selenoheterocyclic Compounds Homologues of Ebselen

“…Hence, the design, synthesis, and evaluation of small-molecule selenium compounds that mimic the biological activity of GPx have been investigated by several groups, and selected examples 2 [28], 3 [29], 4 [30], and 5 [31] are presented in Scheme 2. Various diaryl diselenides [32][33][34][35][36][37][38] and certain types of tellurium compounds as well as dendrimeric and cyclodextrin-derived organochalcogen catalysts that emulate GPx have also been reported [39][40][41][42][43][44][45][46].…”