Disease relevance of oximes

• Demonstration of free radical generation in "stunned" myocardium of intact dogs with the use of the spin trap alpha-phenyl N-tert-butyl nitrone [1].
• We used a murine syngeneic bone marrow transplant (BMT) model, in which administration of anti-CD40 antibody early after BMT results in overproduction of interleukin-12 (IL-12) and interferon-gamma (IFN-gamma), and lethal gut toxicity to examine the protective effect of the spin trap inhibitor, alpha phenyl-tert-butyl nitrone (PBN) [2].
• Stilbazulenyl nitrone, a novel antioxidant, is highly neuroprotective in focal ischemia [3].
• alpha-Phenyl-tert-butyl nitrone (PBN) is a nitrone spin trap, which has shown efficacy in animal models of oxidative stress, including stroke, aging, sepsis, and myocardial ischemia/reperfusion injury [4].
• Phenyl-{alpha}-tert-Butyl Nitrone Reverses Mitochondrial Decay in Acute Chagas' Disease [5].

Psychiatry related information on oximes

• 1-aryl-3-(4-pyridine-2-ylpiperazin-1-yl)propan-1-one oximes as potent dopamine D4 receptor agonists for the treatment of erectile dysfunction [6].
• The in vivo cytoprotective effects of alpha-phenyl-t-butyl nitrone against striatal excitotoxic lesions suggest that antioxidants could be used as potential neuroprotective agents in Huntington's disease, which has been suggested to involve excitotoxicity [7].
• PBN (alpha-phenyl-tert-butyl nitrone), one of the more widely used nitrones for this purpose, has been shown to have potent pharmacologic activities in models of a number of aging-related diseases, most notably the neurodegenerative diseases of stroke and Alzheimer's disease [8].
• The carboxamides Ie and IVe were obtained from the oximes Ic and IVc via the cyano derivatives Id and IVd [9].

High impact information on oximes

• Complex V-deficient fibroblasts, which showed a high SOD induction and stained positive for all studied apoptosis markers, were successfully rescued by perfluoro-tris-phenyl nitrone, an antioxidant spin-trap molecule [10].
• Male Wistar rats were fed a choline-deficient, L-amino acid-defined (CDAA) diet alone or in combination with a nitrone-based free radical trapping agent, phenyl N-tert-butyl nitrone (PBN) in the drinking water at the concentrations of 0.013, 0.065, and 0.130% for 12 weeks [11].
• This nitrone (4) reacts with alpha-hydroxyethyl radical with a second order rate constant of 1.7 x 10(5) M-1 s-1 to give a characteristic ESR spectrum [12].
• When LPO reacted with GSH in the presence of DMPO, we detected an LPO radical-derived DMPO nitrone adduct using enzyme-linked immunosorbent assay and Western blotting [13].
• We investigated the anti-apoptotic effects of intracellular and extracellular nitric oxide (*NO) donors, iron chelators, cell-permeable superoxide dismutase (SOD), glutathione peroxidase mimetics, and nitrone spin traps [14].

Chemical compound and disease context of oximes

• Neuroprotective effects of a novel nitrone, NXY-059, after transient focal cerebral ischemia in the rat [15].
• N-tert-butyl-alpha-phenylnitrone (PBN), a widely used nitrone-based free radical trap was recently shown to prevent acetylcholinesterase (AChE) inhibitors induced muscle fasciculations and brain seizures while being ineffective against glutamergic or cholinergic receptor agonist induced seizures [16].
• Necrosis of the substantia nigra, pars reticulate, in flurothyl-induced status epilepticus is ameliorated by the spin trap alpha phenyl-N-tert-butyl nitrone [17].
• The nitrone protected these aquatic animals against the lethal toxicity of hydrogen peroxide and doxorubicin and greatly enhanced their survival when co-administered with these oxidotoxins [18].
• Effect of traumatic brain injury and nitrone radical scavengers on relative changes in regional cerebral blood flow and glucose uptake in rats [19].

Biological context of oximes

• N-t-butyl hydroxylamine, a hydrolysis product of alpha-phenyl-N-t-butyl nitrone, is more potent in delaying senescence in human lung fibroblasts [20].
• Therefore, in our study, we selected 11 acyclic and cyclic nitrone spin traps with diverse properties to determine their pharmacokinetics in mice [21].
• In a detailed analysis of the substrate specificities of the recombinant enzymes heterologously expressed in yeast (Saccharomyces cerevisiae), we show that aliphatic oximes derived from chain-elongated homologs of methionine are efficiently metabolized by CYP83A1, whereas CYP83B1 metabolizes these substrates with very low efficiency [22].
• Further, they suggest that the improved performance of dimeric oximes is conferred by two-site binding with one oxime pointing toward the diisopropyl ester at the catalytic site of hAChE and the other anchored at the peripheral site [23].
• The nitrone slowly decomposed in acidic aqueous solution at ambient temperature and also underwent in-source, thermal-induced hydrolysis during electrospray ionization mass spectrometric analysis [24].

Anatomical context of oximes

• In addition, we were able to demonstrate the presence of hemoglobin radical-derived nitrone adducts inside red blood cells exposed to H2O2 and DMPO [25].
• Studies of the transfer constant of [14C]NXY-059 showed that, in contrast to PBN, this more soluble nitrone penetrates the blood-brain barrier less extensively [15].
• The results showed that myeloperoxidase-catalyzed redox cycling of phenol in HL-60 cells led to intracellular formation of glutathionyl radicals detected as GS-DMPO nitrone [26].
• Indeed, in HOCl-treated hepatocytes, catalase and protein-DMPO nitrone adducts were colocalized in the cells' peroxisomes [27].
• The affinities of these oximes were tested in homogenates of cerebral cortex, heart, and submandibulary glands from rats using [3H]pirenzepine and [3H]-N-methylscopolamine as radioligands [28].

Associations of oximes with other chemical compounds

• Furthermore, antiapoptotic antioxidants (e.g. FeTBAP, ebselen, and alpha-phenyl-tert-butyl nitrone) inhibited DOX-induced eNOS transcription [29].
• Methyl radicals were identified by spin-trapping experiments with alpha-(4-pyridyl-1-oxide)-N-tert-butyl nitrone and tert-nitrosobutane [30].
• The nitrone complexes [(eta(5)-C(5)Me(5))M{(R)-Prophos}(nitrone)](SbF(6))(2) (M = Rh, nitrone = 1-pyrrolidine N-oxide (5), 2,3,4,5,-tetrahydropyridine N-oxide (6), 3,4-dihydroisoquinoline N-oxide (7); M = Ir, nitrone = 1-pyrrolidine N-oxide (8)) have been isolated and characterized including the X-ray crystal structure of compounds 6 and 8 [31].
• We have previously reported that phenyl N-tert-butyl nitrone (PBN) inhibits the induction of inducible nitric oxide synthase (iNOS) and, thus, prevents the overproduction of nitric oxide (NO), resulting in the reduction of endotoxin-mediated death in mice [32].
• 5,5-Dimethyl-1-pyrroline N-oxide (DMPO) spin trapping in conjunction with antibodies specific for the DMPO nitrone epitope was used on hydrogen peroxide-treated sperm whale and horse heart myoglobins to determine the site of protein nitrone adduct formation [33].
• O-Trityl oximes of 5- and 6-iodoaldehydes undergo radical cyclization to produce oximes when treated in refluxing tetrahydrofuran (THF) with Bu3SnH, 1,1'-azobis(cyclohexanecarbonitrile), i-Pr2NEt, and diphenyl diselenide (PhSeSePh) [34].

Gene context of oximes

• CYP83A1 and CYP83B1, two nonredundant cytochrome P450 enzymes metabolizing oximes in the biosynthesis of glucosinolates in Arabidopsis [22].
• The ability of CYP83A1 to metabolize aromatic oximes, albeit at small levels, explains the presence of indole glucosinolates at various levels in different developmental stages of the CYP83B1 knockout mutant, rnt1-1 [22].
• The difference in the efficacy of both NO-generating compounds could be due to the additional release of superoxide by SIN-1, since superoxide dismutase and the nitrone 5,5'-dimethyl pyrroline-1-oxide markedly inhibited the SIN-1-induced covalent binding of NAD+ to GAPDH [35].
• The results suggest that aliphatic primary amines are efficiently sequentially N-oxygenated in the presence of human liver microsomes to hydroxylamines and then to oximes mainly by the human flavin-containing monooxygenase [36].
• A cyclooxygenase (COX)-1 inhibitory effect has also been reported for 4'-piperidinoacetophenone and 4'-morpholinoacetophenone oximes and their O-acyl derivatives [37].

Analytical, diagnostic and therapeutic context of oximes

• Electron paramagnetic resonance spectroscopy using alpha-(4-pyridyl-1-oxide)-N-tert-butyl nitrone as a spin trapping agent showed an enhanced free radical generation due to the addition of OA and most of the analogs [38].
• In the present study, the formation of nitrone adducts on hemoglobin was shown to depend on the oxidation state of the iron heme, the concentrations of H2O2 and DMPO, and time as determined by enzyme-linked immunosorbent assay (ELISA) and by Western blotting [25].
• VP-16 redox-cycling by purified myeloperoxidase (in the presence of GSH) or by myeloperoxidase activity in HL60 cells is accompanied by generation of thiyl radicals, GS(.), determined by HPLC assay of 5, 5-dimethyl-1-pyrroline glytathionyl N-oxide glytathionyl nitrone adducts [39].
• These data demonstrate that on-line determinations of nitrone spin-trap brain penetration/levels can be carried out accurately using in vivo microdialysis [40].
• Now the development of an immunoassay for the nitrone adducts of protein radicals brings the power of immunological techniques to bear on free radical biology [41].

References