Hormetic Effects of Binaphthyl Phosphonothioates as Pro-oxidants and Antioxidants.

Organophosphorous compounds with such a wide variety in structure, application, and biochemical activities include pesticides, herbicides, nerve agents, medicines, reagents in organic chemistry, and additives for polymers. Binaphthyl phosphono-, phosphorothioates, and their derivatives, are useful chiral catalysts for various asymmetric reactions and are expected to act as heavy metal scavengers. In this study, we aimed to evaluate the neurotoxicity and biochemical properties of a new series of binaphthyl phosphonothioates called KK compounds using the mouse hippocampal HT22 cells. Despite negligible structural difference, the compounds exhibited differential general cytotoxic activity which was independent of acetylcholine esterase inhibition; on the other hand, all compounds tested prevented endogenous oxidative stress by suppressing generation of reactive oxygen species. Among them, KK397, KK387, KK410, and KK421 showed hormesis, i.e., biphasic dose responses to endogenous oxidative stress, characterized by beneficial effect at low dose and toxic effect at high dose. At cytotoxic concentrations, these compounds were potent radical generators and activated intracellular signaling molecules such as the p38 mitogen-activated protein kinase, c-Jun NH-terminal kinase, growth arrest- and DNA damage-inducible gene 153, X-box binding protein 1, and heme oxygenase 1, which are preferentially activated by cell stress-inducing signals, including oxidative and endoplasmic reticulum stress. These findings indicated that novel binaphthyl phosphonothioates can exhibit multiple biochemical properties, functioning as antioxidants and/or pro-oxidants, depending on the concentration, and chemical modification of binaphthyl organophosphorus compounds endowed them with unique characteristics and multiple beneficial functions.