Suppressive effect of 1,4-anhydro-4-seleno-D-talitol (SeTal) on atopic dermatitis-like skin lesions in mice through regulation of inflammatory mediators.

BACKGROUND: Atopic dermatitis (AD) is a multifactorial chronic inflammatory disease that affects ∼20 % of children and 3% of adults globally and is generally treated by the topical application of steroidal drugs that have undesirable side-effects. The development of alternative therapies is therefore an important objective. The present study investigated the effects of topical treatment with a novel water-soluble selenium-containing carbohydrate derivative (4-anhydro-4-seleno-D-tatitol, SeTal) on the symptoms and inflammatory parameters in an AD mouse model. METHODS: Mice were sensitized by applying 2,4-dinitrochlorobenzene (DNCB) to their dorsal skin on days 1-3, then further challenged on their ears and dorsal skin on days 14, 17, 20, 23, 26, and 29. SeTal (1 and 2%) or hydrocortisone (1%) was applied topically to the backs of the mice from days 14-29, and skin severity scores and scratching behavior determined on day 30. The mice were euthanized, and their ears and dorsal skin removed to quantify inflammatory parameters, edema, myeloperoxidase (MPO) activity, and AD-associated cytokines (tumor necrosis factor alpha (TNF-α), interleukins (IL)-18, and IL-33). RESULTS: DNCB treatment induced skin lesions and increased the scratching behavior, ear edema, MPO activity (ear and dorsal skin), and cytokine levels in dorsal skin. Topical application of SeTal improved inflammatory markers (cytokine levels and MPO activity), cutaneous severity scores, and scratching behavior. CONCLUSION: The efficacy of SeTal was satisfactory in the analyzed parameters, showing similar or better results than hydrocortisone. SeTal appears to be therapeutically advantageous for the treatment and control of AD.

Catalytic oxidant scavenging by selenium-containing compounds: Reduction of selenoxides and N-chloramines by thiols and redox enzymes.

Myeloperoxidase produces strong oxidants during the immune response to destroy invading pathogens. However, these oxidants can also cause tissue damage, which contributes to the development of numerous inflammatory diseases. Selenium containing compounds, including selenomethionine (SeMet) and 1,4-anhydro-5-seleno-D-talitol (SeTal), react rapidly with different MPO-derived oxidants to form the respective selenoxides (SeMetO and SeTalO). This study investigates the susceptibility of these selenoxides to undergo reduction back to the parent compounds by intracellular reducing systems, including glutathione (GSH) and the glutathione reductase and thioredoxin reductase systems. GSH is shown to reduce SeMetO and SeTalO, with consequent formation of GSSG with apparent second order rate constants, k2, in the range 103-104M-1s-1. Glutathione reductase reduces both SeMetO and SeTalO at the expense of NADPH via formation of GSSG, whereas thioredoxin reductase acts only on SeMetO. The presence of SeMet and SeTal also increased the rate at which NADPH was consumed by the glutathione reductase system in the presence of N-chloramines. In contrast, the presence of SeMet and SeTal reduced the rate of NADPH consumption by the thioredoxin reductase system after addition of N-chloramines, consistent with the rapid formation of selenoxides, but only slow reduction by thioredoxin reductase. These results support a potential role of seleno compounds to act as catalytic scavengers of MPO-derived oxidants, particularly in the presence of glutathione reductase and NADPH, assuming that sufficient plasma levels of the parent selenoether can be achieved in vivo following supplementation.

7-Selenabicyclo[2.2.1]heptane.

Thermolysis of a benzene solution of N-[4-(p-(methoxybenzyl)seleno)cyclohexanoyl]-N,S-dimethyldithiocarbonate affords the hitherto unknown 7-selenabicyclo[2.2.1]heptane in 48% conversion and in 20% yield after chromatography. G3(MP2)-RAD calculations predict a rate constant of 5 × 10(4) s(-1) at 80 °C (3.8 × 10(6) s(-1) at 200 °C) for the intramolecular homolytic substitution process involved in this cyclization.

Synthesis and antioxidant capacity of 5-selenopyranose derivatives.

Described is a convenient method for the syntheses of sulfur and selenium containing carbohydrate derivatives of L-gulodeoxynojirimycin and the corresponding C-5 epimer D-mannodeoxynojirimycin. The key step in the synthesis of the latter involves epimerisation of the C-5 hydroxyl group by an oxidation followed by stereo-selective reduction to obtain the desired D-sugar derivative. Both derivatives displayed a dose-dependent prevention of the oxidation of methionine residues on human plasma proteins induced by the inflammatory oxidant hypochlorous acid. The seleno-analogues were considerably more active than their thio-equivalents.

First-principles prediction of rate coefficients for free-radical cyclization reactions at selenium.

High-level ab initio calculations of the barriers, enthalpies, and rate coefficients for the intramolecular cyclization reactions of *CH(2)CH(2)CH(2)CH(2)SeR (R = Me, n-Bu, s-Bu, t-Bu, Bn, Bz, Ph(2)CH) and *CH(2)CH(2)CH(2)CH(2)CHCH(2) have been performed at the G3(MP2)-RAD level. The calculated rate coefficients show excellent agreement with experiment (to within a factor of 5 or better), although this might be due, in part, to a systematic cancelation of order-of-magnitude errors in the corresponding Arrhenius parameters. The intramolecular cyclizations at selenium were found to be energetically favorable processes that occur with synthetically accessible rate coefficients on the order of 10(4)-10(6) s(-1) at 294 K. These values are largely governed by the stabilization energy of the leaving radical, though with contributions from steric and polar effects.

Preparation of 2,3-dihydroselenolo[2,3-b]pyridines and related compounds by free-radical means.

Photolysis of the thiohydroximate ester derivative 21 of 2-carboethoxy-2-(2-(benzylseleno)pyridin-3-yl)tridecylcarboxylic acid (20) affords 2-dodecyl-2-carboethoxy-2,3-dihydroselenolo[2,3-b]pyridine (22) in 89% yield in a process presumably involving intramolecular homolytic substitution by a tertiary alkyl radical at selenium with loss of a benzyl radical. Alternatively, rearrangement of O-(omega-haloalkyl)esters 34 of 2-carboethoxy-N-hydroxypyridine-2-selone affords azonianaphthalenium halides 37 in 79% yield.

Preparation of novel selenopenams by intramolecular homolytic substitution.

Photolyses of the thiohydroximate ester derivatives 13 and 21 of the 4- (benzyl-seleno)-2-azetidinoines 7 and 20, afford the 1-aza-7-oxo-4-selenabicyclo- [3.2.0]heptane ring systems 14 and 21 in good to moderate yield in processes that presumably involve intramolecular homolytic substitution at selenium with expulsion of benzyl radical. Extension of this methodology to the preparation of derivatives 24 of 12,2a-dihydro-1H,8H-azeto[2,1-b][1,3]benzoselenazin-1-one (22) is also described.

Toward pyridine-fused selenium-containing antioxidants.

Photolysis of the thiohydroximate ester derivative 21 of 2-carboethoxy-2-(2- (benzylseleno)pyridin-3-yl)tridecylcarboxylic acid (20) affords 2-dodecyl-2- carboethoxy-2,3-dihydroselenolo[2,3-b]pyridine (22) in 89% yield in a process presumably involving intramolecular homolytic substitution by a tertiary alkyl radical at selenium with loss of a benzyl radical. Work toward extending this methodology to the preparation of pyridine-fused selenium analogues of antioxidants is described.