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 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)-1 H-benzoimidazole-2-selenone (1) which show an 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 (GPx)-like activity, at cellular level of HO concentration, with an 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-(CH)OH substituent through neighboring group participation (deselenization step), resulted the controlled synthesis of various types of CuSe nanocrystals (nanodiscs, nanocubes and nanosheets) and tetragonal CuSe 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 Mn, Fe, Co, Ni or Zn fail 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 concentrations of these genes is observed in cells treated with Cu alone, indicating that 1 plays a significant role in Cu homoeostasis in hepatocyte.