Regenerable, multifunctional ebselenol antioxidants were prepared that could quench peroxyl radicals more efficiently than α-tocopherol. These compounds act as better mimics of the glutathione peroxidase enzymes than ebselen. Production of reactive oxygen species (ROS) and reactive nitrogen species (RNS) in human mononuclear cells was considerably decreased upon exposure to the organoselenium compounds. At a concentration of 25 μm, the ebselenol derivatives showed minimal toxicity in pre-osteoblast MC3T3 cells.

Autoxidation, the free radical chain reaction that nominally inserts O into hydrocarbons to give peroxides, is primarily responsible for the degradation of all organic materials. Peroxyl radicals propagate autoxidation mainly by abstraction of labile H-atoms from the hydrocarbons, whereas radical-trapping antioxidants (RTAs) inhibit autoxidation by donating an H-atom to the peroxyl radical to give a nonpropagating radical. As such, a detailed understanding of the kinetics and thermodynamics of H-atom transfer (HAT) reactions to peroxyl radicals, and the effects of sterics, electronics, and medium thereupon, is key to understanding the mechanisms and products of autoxidation and the ability of RTAs to inhibit it. Due to their relatively weak O-H and N-H bonds, phenols and aromatic amines have long been utilized as RTAs, but only phenols have been extensively optimized to maximize their reactivity. Amines offer greater structural variability owing to their trivalent central nitrogen atom. Simply linking the two aromatic rings of a diarylamine to afford a phenoxazine offers profound differences in HAT reactivity: 1000-times greater than diphenylamine and 10-fold more reactive than α-tocopherol, Nature's optimized phenolic RTA. Thus, phenoxazines are an exciting scaffold for RTA development. Indeed, we have recently shown that ring substitution of phenoxazine or 2,4-diazaphenoxazine can yield compounds that undergo barrierless HAT reactions with peroxyl radicals. Amines also have the distinct advantage that they can react with peroxyl radicals to yield nitroxides, which can inhibit autoxidation in a catalytic manner utilizing the substrate itself as the stoichiometric reductant. Herein we provide an account of our recent efforts to understand how they manage this feat, which have revealed at least four mechanisms depending on the specific reaction conditions (i.e., saturated hydrocarbons at elevated temperatures, unsaturated hydrocarbons, acidic media, aqueous media/lipid dispersions). We also reiterate how their impressive RTA activity translates from solution to mammalian cell culture, wherein we have demonstrated that diarylamines and their derived nitroxides are potent inhibitors of ferroptosis, a recently characterized form of cell death associated with lipid peroxidation (autoxidation). In addition to phenols and amines, organosulfur compounds have long been used as antioxidants. The prevailing view has been that they undergo ionic reactions with product peroxides, preventing the initiation of further chain reactions. In recent years, we have found that many organosulfur compounds exhibit very good RTA activity. In particular, sulfenic acids (RSOH) and hydropersulfides (RSSH) are found to be among the best HAT agents known, particularly to peroxyl radicals where secondary orbital interactions are found to play a significant role. Consequently, oxidation of the sulfenic acid to a sulfinic acid greatly diminishes its HAT reactivity to peroxyls. Polysulfides and their oxides also undergo direct reactions with pero...

Novel azo-bis-ebselen compounds 7 were prepared by reduction of 7-nitro-2-aryl-1,2-benzisoselenazol-3(2H)-ones 3 and 6 with sodium benzenetellurolate, NaTeC6H5, and by reaction of 2-bromo-3-nitrobenzamides with Na2Se2. The X-ray structure of 7b showed that the molecule, due to strong intramolecular secondary Se···N interactions, is completely planar. Azo-compounds 7 upon further reaction with NaTeC6H5 were reductively cleaved to provide two equivalents of the corresponding aromatic amine. The weak Se─N bond was not stable enough to survive the reaction conditions and diselenides 8 were isolated after work-up. Whereas azo-bis-ebselens 7 were poor mimics of the glutathione peroxidase (GPx)-enzymes, nitroebselens 3, 6 and 11b and diselenides 8 were 3-6 fold more active than ebselen. Based on 77 Se NMR spectroscopy, a catalytic cycle for diselenide 8b, involving aminoebselen 14, was proposed. As assessed by chemiluminescence measurements, the good GPx-mimics could reduce production of reactive oxygen species (ROS) in stimulated human mononuclear cells more efficiently than Trolox. No toxic effects of the compounds were seen in MC3T3-cells at 25 M.

Herein we demonstrate that copper(II)-diacetylbis(N 4 -methylthiosemicarbazone)(CuATSM), clinical candidate for the treatment of ALS and Parkinson's disease, is a highly potent radical-trapping antioxidant (RTA) and inhibitor of (phospho)lipid peroxidation. In THF autoxidations, CuATSM reacts with THF-derived peroxyl radicals with k inh = 2.2 × 10 6 M −1 s −1 roughly 10-fold greater than α-tocopherol (α-TOH), Nature's best RTA. Mechanistic studies reveal no H/D kinetic isotope effects and a lack of rate-suppressing effects from Hbonding interactions, implying a different mechanism from α-TOH and other canonical RTAs, which react by H-atom transfer (HAT). Similar reactivity was observed for the corresponding Ni 2+ complex and complexes of both Cu 2+ and Ni 2+ with other bis(thiosemicarbazone) ligands. Computations corroborate the experimental finding that rate-limiting HAT cannot account for the observed RTA activity and instead suggest that the reversible addition of a peroxyl radical to the bis(thiosemicarbazone) ligand is responsible. Subsequent HAT or combination with another peroxyl radical drives the reaction forward, such that a maximum of four radicals are trapped per molecule of CuATSM. This sequence is supported by spectroscopic and mass spectrometric experiments on isolated intermediates. Importantly, the RTA activity of CuATSM (and its analogues) translates from organic solution to phospholipid bilayers, thereby accounting for its (their) ability to inhibit ferroptosis. Experiments in mouse embryonic fibroblasts and hippocampal cells reveal that lipophilicity as well as inherent RTA activity contribute to the potency of ferroptosis rescue, and that one compound (CuATSP) is almost 20-fold more potent than CuATSM and among the most potent ferroptosis inhibitors reported to date.

One of the vitamin B6 vitamers, pyridoxine, was modified to incorporate selenium in various oxidation states in place of the methyl group in position 2. Such compounds were conveniently accessed by treatment of bis-4,5-(carboethoxy)-2-iodo-3-pyridinol with disodium diselenide and LiAlH4 -reduction. After work-up, selone 7 was isolated in good yield as an air-stable crystalline material. Hydrogen bonding to the neighboring hydroxyl group, as revealed by the short intramolecular Se⋅⋅⋅H distance in the crystal structure is likely to provide extra stabilization to the compound. Computational studies showed that selone 7 is more stable than the corresponding selenol tautomer by 12.2 kcal mol(-1) . Hydrogen peroxide oxidation of the selone 7 afforded diselenide 12, and, on further oxidation, seleninic acid 13. Treatment of the seleninic acid with thiophenol provided an isolable selenosulfide 14. The glutathione peroxidase-like properties of the pyridoxine-derived compounds were assessed by using the coupled reductase method. Seleninic acid 13 was found to be twofold more active than ebselen. The chain-breaking capacity of the pyridoxine compounds were studied in a water/chlorobenzene membrane model containing linoleic acid as an oxidizable substrate and N-acetylcysteine as a thiol reducing agent. Diselenide 15 could match α-tocopherol when it comes to reactivity towards peroxyl radicals and inhibition time.