Ebselen [2-phenyl-1,2-benzisoselenazol-3(2H)-one], a selenoorganic compound with glutathione peroxidase-like activity is used in clinical trials against stroke. Human and bovine TrxR catalyzed the reduction of ebselen to ebselen selenol by NADPH with an apparent K M-value of 2.5 M and a kcat of 588 min ؊1 . The addition of thioredoxin (Trx) stimulated the TrxR-catalyzed reduction of ebselen several-fold. This result was caused by a very fast oxidation of reduced Trx by ebselen with a rate constant in excess of 2 ؋ 10 7 M ؊1 s ؊1 . This rate is orders of magnitude faster than the reaction of dithiol Trx with insulin disulfides. Ebselen competed with disulfide substrates for reduction by Trx and, therefore, acted as an inhibitor of protein disulfide reduction by the Trx system. The inherent H2O2 reductase activity of mammalian TrxR dependent on its active-site selenocysteine residue was stimulated 10-fold by 2 M ebselen and 25-fold in the additional presence of 5 M Trx. Furthermore, the apparent KM-value of TrxR for H2O2 was lowered 25-fold to about 100 M. Our results demonstrate that ebselen is a TrxR peroxidase which, in the presence of Trx, acted as a mimic of a peroxiredoxin. The activity with TrxR and oxidation of reduced Trx offer mechanistic explanations for the in vivo effects of ebselen as an antioxidant and anti-inflammatory agent. Our results demonstrate that the mechanism of action of ebselen may be predominantly via the Trx system rather than via glutathione.selenol ͉ inflammation ͉ signal transduction ͉ oxidative stress ͉ redox regulation E bselen [2-phenyl-1,2-benzisoselenazol-3(2H)-one] is a lipidsoluble seleno-organic compound that exhibits a weak glutathione peroxidase (GPx)-like activity in vitro (1-6). The specificity for substrates ranges from H 2 O 2 to smaller organic hydroperoxides and includes membrane-bound phospholipid and cholesterylester hydroperoxides. Because ebselen is effective against membrane hydroperoxides, it inhibits both nonenzymatic and enzymatic lipid peroxidation in cells and has anti-inflammatory activity in various animal models (5, 6). Ebselen also will directly inhibit inflammation-related enzymes such as 5-lipoxygenase, nitric oxide synthases, NADPH oxidase, protein kinase C, and ATPase by chemically modifying an SH-group forming a selenosulfide complex (5, 6).Because of its anti-inflammatory properties, ebselen has been used in the treatment of patients with acute ischemic stroke (7,8) or delayed neurological deficits after aneurysmal subarachnoid hemorrhage (9). The results of these clinical trials indicate the benefit of ebselen as a neuroprotective agent. Also, recent animal studies show neuroprotective, antioxidant, and antiinflammatory actions of ebselen in a rodent model of permanent middle as well as transient cerebral artery occlusion (10-13).Thioredoxin (Trx) reductase (TrxR) is a dimeric FADcontaining enzyme that catalyzes the NADPH-dependent reduction of the active-site disulfide in oxidized Trx (Trx-S 2 ) to give a dithiol in reduced Trx [Trx-(SH) 2 ] (14...
Increasing antibiotic resistance makes the identification of new antibacterial principles an urgent task. The thioredoxin system including thioredoxin reductase (TrxR), thioredoxin (Trx), and NADPH plays critical roles in cellular DNA synthesis and defense against oxidative stress. Notably, TrxR is very different in structure and mechanism in mammals and bacteria. Ebselen [2-phenyl-1,2 benzisoselenazol-3(2H)-one], a well-known antioxidant and a substrate for mammalian TrxR and Trx, is rapidly bacteriocidal for methicillin-resistant Staphylococcus aureus by an unknown mechanism. We have discovered that ebselen is a competitive inhibitor of Escherichia coli TrxR with a Ki of 0.52 ± 0.13 μM, through reaction with the active site dithiol of the enzyme. Bacteria lacking glutathione (GSH) and glutaredoxin, in which TrxR and Trx are essential for DNA synthesis, were particularly sensitive to ebselen. In growth-inhibited E. coli strains, Trx1 and Trx2 were oxidized, demonstrating that electron transfer via thioredoxin was blocked. Ebselen and its sulfur analog ebsulfur were bactericidal for GSH-negative pathogens. Ebsulfur inhibited a clinically isolated Helicobacter pylori strain with a minimum inhibitory concentration value as low as 0.39 μg/ml. These results demonstrate that bacterial Trx and TrxR are viable antibacterial drug targets using benzisoselenazol and benzisothiazol derivates.
The antioxidant mechanism of ebselen involves recently discovered reductions by mammalian thioredoxin reductase (TrxR) and thioredoxin (Trx) forming ebselen selenol. Here we describe a previously unknown reaction; ebselen reacts with its selenol forming an ebselen diselenide with a rate constant of 372
Product studies have been undertaken on the OH ؒ radical-induced oxidation of glutathione in N 2 Osaturated aqueous solutions. Ammonia has been found to be a prominent product with G values around 2.5-2.9 × 10 Ϫ7 J mol Ϫ1 from pH 6 to 10.5. The ammonia is considered to be a product of the disproportionation reaction of the -amino carbon-centred radicals, formed via the intramolecular transformation of glutathione thiyl radicals. At pH ca. 4-6, the ammonia yield decreases due to the fact that the transformation reaction slows down with decreasing pH and eventually comes into competition with bimolecular recombination. From the pH dependence of the ammonia yield curve, the equilibrium constant between the glutathione thiyl radical and the -amino carbon-centred radical is deduced to be >10 4 . The strength of the C-H bond to the NH 2 and CO 2 Ϫ groups is thus <343 kJ mol Ϫ1 . The corresponding bond energy of the C-H bond to the NH 2 and CO 2 H groups is estimated to be <329 kJ mol Ϫ1 . Based on the ammonia formation, consumption of free SH groups and the HPLC chromatograms obtained at different pH values after -irradiation of N 2 O-saturated glutathione solutions, the overall reaction mechanism concerning the fate of glutathione thiyl radicals is proposed. This mechanism and its kinetics indicate that the intramolecular transformation is one of the principal pathways of self-removal of glutathione thiyl radicals, which is formed in various repair processes, in both anaerobic and aerobic conditions.
A metal-free ring opening/halogenation of cycloalkanols, which combines both PPO/TBAX oxidant system and blue LEDs irradiation, is presented. This method produces diverse γ, δ, and even more remotely halogenated ketones in moderate to excellent yields under mild conditions. Interestingly, experimental and computational studies demonstrate the novel ring size-dependent concerted/stepwise (four-/five- to eight-membered rings) hydrogen atom transfer-electron transfer induced by Brønsted base-tethered acyloxy radical, which indicates distinct advantages brought by the cyclic structure of diacyl peroxides.
Over the past decade, the effectiveness of i-PrMgCl·LiCl has been constantly highlighted by a number of research groups. Its enhanced nucleophilicity brings prosperity to highly functionalized Grignard reagents, other useful bimetallic (alkali-metal) agents and nucleophilic alkylation products under mild reaction conditions. In this feature article, a comprehensive, systematical and in-depth overview of i-PrMgCl·LiCl is provided in a multidisciplinary idea. It involves the structural and kinetic perspectives of i-PrMgCl·LiCl as well as its unique reactivity and selectivity, with knowledge of the former helping to rationalize trends of the later.
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