Phenylalkyl isoselenocyanates vs phenylalkyl isothiocyanates: thiol reactivity and its implications

Phenylalkyl isoselenocyanate (ISC) compounds were recently designed in our laboratory by incorporating the anticancer element selenium into a panel of phenylalkyl isothiocyanates (ITCs), known to have anticancer properties. A structural activity investigation was carried out to compare the ISC and ITC panels. Cell viability assay and Annexin V staining for apoptosis showed ISC compounds to be more potent in killing A549 lung adenocarcinoma cells. Both ITCs and ISCs were able to deplete reduced glutathione (GSH) in cells, ISCs more rapidly, but ITCs to a greater extent. ISC compounds had a higher rate of reaction to thiol (-SH) groups as determined by pseudo first order kinetics than the corresponding carbon chain length ITC. The equilibrium concentrations of the GSH and protein thiol conjugates did not differ significantly when comparing sulfur to selenium compounds of the same carbon chain length, and did follow the same trend of displaying decreasing reactivity with increasing carbon chain length for both ITCs and ISCs. Furthermore, only ITCs were able to induce cell cycle arrest, suggesting that protein targets inside the cell may differ for the S and Se panels. Finally, the panels were tested for their ability to redox cycle when reacted with GSH to form superoxide and other reactive oxygen species (ROS). ISC compounds showed a much greater ability to redox cycle than corresponding ITCs, and were able to induce higher levels of ROS in A549 cells. Also, the direct pro-apoptotic effects of ISCs and ITCs were inhibited by GSH and potentiated by depletion of intracellular GSH by buthionine sulfoximine. In conclusion, our studies suggest that the redox-cycling capabilities of ISCs and thus generation of higher levels of ROS may be contributing to the increased cytotoxicity of ISC compounds in A549 cells, compared to that of the corresponding ITCs.