Hormetic Effects of Binaphthyl Phosphonothioates as Pro-oxidants and Antioxidants

Abstract

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 2terminal 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 prooxidants, depending on the concentration, and chemical modification of binaphthyl organophosphorus compounds endowed them with unique characteristics and multiple beneficial functions.

3′5-Dimaleamylbenzoic Acid Attenuates Bleomycin-Induced Pulmonary Fibrosis in Mice

“…Our results showed better effects of 3′5-DMBA on pulmonary fibrosis at a low dose of 6 mg/kg compared to the high dose of 10 mg/kg. Previously, concentration-dependent variation in therapeutic effects has been reported as a response to stimulation at low doses and inhibition at high doses in compensation for mild stress; a phenomenon termed hormesis [ 52 ]. For example, the flavonoid quercetin has been shown to exert dual effects depending on the dose administered.…”

“…Nitrated fatty acid CXA-10 exhibits anti-inflammatory, antifibrotic, and renal injury-limiting effects with a hormetic dose–response profile [ 54 ]. Similarly, binaphthyl phosphonothioates, compounds with a pro-oxidant character, exhibit this hormetic behavior [ 52 ]. The beneficial effect of low doses of antifibrotic has been demonstrated in clinical trials with pirfenidone; in this regard, decreasing the dose of pirfenidone shows an improvement in forced vital capacity and survival of patients compared to the standard dose [ 55 ].…”

Primary Phosphines and Phosphine Oxides with a Stereogenic Carbon Center Adjacent to the Phosphorus Atom: Synthesis and Anti-Markovnikov Radical Addition to Alkenes

“…The stereochemistry on a phosphorus atom has not received much attention, despite the fact that the introduction of at least three different substituents to the phosphorus atom gives rise to the stereogenic center on the phosphorus atom. During the course of our studies on main group chemistry [39,40], we have intensively studied the synthesis and applications studies on main group chemistry [39,40], we have intensively studied the synthesis and applications of organophosphorus compounds with a binaphthyl group [41][42][43][44][45] and recently reported that the deprotonation and alkylation of phosphonoselenoates and phosphonates with a binaphthyl group creates stereogenic secondary and tertiary carbon centers adjacent to the phosphorus atom with high diastereoselectivity (Scheme 1a,b) [46]. The resulting products are potentially available as precursors of primary phosphines since phosphorus-oxygen bonds are readily reduced to P-H bonds.…”