Copper-Driven Deselenization: A Strategy for Selective Conversion of Copper Ion to Nanozyme and Its Implication for Copper-Related Disorders

Synthetic organic molecules, which can selectively convert excess intracellular copper (Cu) ions to nanozymes with an ability to protect cells from oxidative stress, are highly significant in developing therapeutic agents against Cu-related disorder like Wilson’s disease. Here, we report 1,3-bis­(2-hydroxyethyl)-1H-benzoimidazole-2-selenone (1), which shows a remarkable ability to remove Cu ion from glutathione, a major cytosolic Cu-binding ligand, and thereafter converts it into copper selenide (CuSe) nanozyme that exhibits remarkable glutathione peroxidase-like activity, at cellular level of H₂O₂ concentration, with excellent cytoprotective effect against oxidative stress in hepatocyte. Cu-driven deselenization of 1, under physiologically relevant conditions, occurred in two steps. The activation of CSe bond by metal ion is the crucial first step, followed by cleavage of the metal-activated CSe bond, initiated by the OH group of N–(CH₂)₂OH substituent through neighboring group participation (deselenization step), resulted in the controlled synthesis of various types of Cu_2‑xSe nanocrystals (NCs) (nanodisks, nanocubes, and nanosheets) and tetragonal Cu₃Se₂ NCs, depending upon the oxidation state of the Cu ion used to activate the CSe bond. Deselenization of 1 is highly metal-selective. Except Cu, other essential metal ions, including Mn²⁺, Fe²⁺, Co²⁺, Ni²⁺, or Zn²⁺, failed to produce metal selenide under identical reaction conditions. Moreover, no significant change in the expression level of Cu-metabolism-related genes, including metallothioneines MT1A, is observed in liver cells co-treated with Cu and 1, as opposed to the large increase in the concentrations of these genes observed in cells treated with Cu alone, suggesting the participation of 1 in Cu homeostasis in hepatocyte.