Model mechanisms of sulfhydryl oxidation by methyl- and benzeneseleninic acid, inhibitors of zinc-finger transcription factors

The toxicity of selenium is a major barrier to its application to the prevention of cancer, cardiovascular disease, and other chronic ailments. Organic seleninic acids, as well as other reducible selenium compounds, have been shown to react with biological sulfhydryls to disrupt a variety of biochemical signaling pathways, including transcription and recognition by zinc-finger proteins. Using density-functional theory (DFT) and solvent-assisted proton exchange, the thiol reduction mechanisms of methyl- and benzeneseleninic acid have been modeled as distinct two-step pathways with intermediates as either a seleninyl sulfide or a hypervalent selenurane. The activation barrier for the first step to the selenurane intermediate is 10-13 kcal/mol lower than the seleninyl sulfide. For the second step, reduction of the selenurane is slightly more energetically favorable than for the seleninyl sulfide, primarily due to the implicit solvation correction. The barrier for step two using either intermediate is greater than that of the first step which is consistent with experimental studies that assign the reduction of the intermediate as the rate-determining step. The summary of the DFT results suggest that the reaction pathway is (1) addition of thiol to the seleninic acid to form a short-lived selenurane; (2) rearrangement of the selenurane to the seleninyl sulfide; and (3) reduction of the seleninyl sulfide by the second equivalent of thiol. (C) 2009 Elsevier Inc. All rights reserved.