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1,4-Anhydro-4-seleno-D-talitol (SeTal) is a highly water-soluble selenosugar with interesting antioxidant and skin-tissue-repair properties; it is highly stable in simulated gastric and gastrointestinal fluids and is a potential pharmaceutical ingredient that may be administered orally. Hepatic toxicity is often a major problem with novel drugs and can result in drug withdrawal from the market. Predicting hepatotoxicity is therefore essential to minimize late failure in the drug-discovery process. Herein, we report in vitro studies to evaluate the cytotoxic and genotoxic potential of SeTal in HepG2 and hepatocyte-like differentiated HepaRG cells. Except for extremely high concentrations (10 mM, 68 h-treatment in HepG2), SeTal did not affect the viability of each cell type. While the highest examined concentrations (0.75 and 1 mM in HepG2; 1 mM in HepaRG) were observed to induce primary DNA damage, SeTal did not exhibit clastogenic or aneugenic activity toward either HepG2 or HepaRG cells. Moreover, no significant cytostasis variations were observed in any experiment. The clearly negative results observed in the CBMN test suggest that SeTal might be used as a potential active pharmaceutical ingredient. The present study will be useful for the selection of non-toxic concentrations of SeTal in future investigations., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Carl H. Schiesser reports a relationship with Seleno Therapeutics that includes: board membership. Michael J. Davies reports a relationship with Seleno Therapeutics that includes: board membership. Michael J. Davies and Carl H. Schiesser are major shareholders and Directors of Seleno Therapeutics, and are named as co-inventors on several patents of relevance to the work presented in this article. Michael J. Davies also declares commercial consultancy contracts with Novo Nordisk A/S. These funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish these results. The other authors declare no conflicts of interest with regard to the data presented., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

New compounds and pharmacological strategies offer alternatives for treating chronic skin diseases, such as atopic dermatitis (AD). Here, we investigated the incorporation of 1,4-anhydro-4-seleno-d-talitol (SeTal), a bioactive seleno-organic compound, in gelatin and alginate (Gel-Alg) polymeric films as a strategy for improving the treatment and attenuation of AD-like symptoms in a mice model. Hydrocortisone (HC) or vitamin C (VitC) were incorporated with SeTal in the Gel-Alg films, and their synergy was investigated. All the prepared film samples were able to retain and release SeTal in a controlled manner. In addition, appreciable film handling facilitates SeTal administration. A series of in-vivo/ex-vivo experiments were performed using mice sensitized with dinitrochlorobenzene (DNCB), which induces AD-like symptoms. Long-term topical application of the loaded Gel-Alg films attenuated disease symptoms and pruritus, with suppression of the levels of inflammatory markers, oxidative damage, and the skin lesions associated with AD. Moreover, the loaded films showed superior efficiency in attenuating the analyzed symptoms when compared to hydrocortisone (HC) cream, a traditional AD-treatment, and decreased the inherent drawbacks of this compound. In short, incorporating SeTal (by itself or with HC or VitC) in biopolymeric films provides a promising alternative for the long-term treatment of AD-type skin diseases., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper: [The authors declare that they have no conflicts of interest, except for M.J.D. and C.H.S. who are major shareholders and Directors of Seleno Therapeutics Pty. Ltd., which holds patents on the development and use of SeTal]., (Copyright © 2023 Elsevier B.V. All rights reserved.)

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., (Copyright © 2021 Elsevier GmbH. All rights reserved.)

Chronic low-grade inflammation and oxidative damage are strongly associated with pathologies including cardiovascular disease. As a consequence, there is considerable interest in agents that mitigate damage. Selenium compounds can act as potent protective agents against oxidation due to the high reactivity and nucleophilicity of the selenium atom. 1,4-Anhydro-4-seleno-d-talitol (SeTal, a novel water-soluble selenium-based sugar) is a potent oxidant scavenger in vitro and in human plasma. Here we show that SeTal is highly stable in solutions that mimic biological fluids and the gastrointestinal tract, and is not rapidly degraded or metabolized unlike some other selenium-containing compounds. SeTal remains intact during extended storage, and it rapidly penetrates into, and effluxes from, primary human coronary artery endothelial and smooth muscle cells, but does not induce loss of metabolic activity, or modulate cell survival and growth rates at concentrations ≤2 mM. Steady-state intracellular concentrations can reach 2-10 μM. SeTal affords protection against H 2 O 2 - and HOCl-mediated oxidative damage, with this being independent of the concentration or activities of the selenium-dependent protective enzymes TrxR and GPx. Protection was observed with both concurrent drug and oxidant administration and also (to a lesser extent) with cellular pre-loading. SeTal also affords protection to isolated arterial segments, with the compound decreasing HOCl (50 μΜ) mediated effects on aortic ring relaxation, consistent with the preservation of NO bioavailability. The stability, bioavailability and protective actions of this compound, suggest that it is worthy of further investigation as a protective agent, particularly in the area of cardiovascular disease., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Novel stable tellurium-containing carbohydrate derivatives are prepared from hexitols and pentitols through a double nucleophilic substitution with NaHTe in PEG-400. These tellurosugars react at very high rates with two-electron oxidants, including hypochlorous and peroxynitrous acid, formed at sites of inflammation, and show considerable promise as protective agents against oxidative damage.

Nitric oxide (NO) is an important effector molecule in host defence against bacterial pathogens. The development of fluorescence imaging to monitor NO production in vitro and in vivo will increase our understanding of its biological role. Recently, a novel 'trappable' fluorescent blue 'turn-on' Cu(II)-complexed coumarin-based probe (CB) has been developed to detect NO. In this study, CB was investigated to evaluate its ability to detect NO in macrophages. Using confocal microscopy, NO was successfully detected in macrophages in the presence of stimuli that induce nitric oxide synthase (iNOS), the enzyme responsible for production of NO. The time dependence and subcellular compartmentalisation of CB in macrophages were evaluated. The probe can be trapped within cells and reacts directly and specifically with NO, rendering it a promising tool for imaging NO in response to pharmacological agents that modulate its level, for example during bacterial infections., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

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, k 2 , in the range 10 3 -10 4 M -1 s -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., (Copyright © 2017. Published by Elsevier B.V.)

Hyperglycaemia increases the generation of reactive oxidants in blood vessels and is a major cause of endothelial dysfunction. A water-soluble selenium-containing sugar (1,4-Anhydro-4-seleno-d-talitol, SeTal) has potent antioxidant activity in vitro and is a promising treatment to accelerate wound healing in diabetic mice. One possible mechanism of SeTal action is a direct effect on blood vessels. Therefore, we tested the hypothesis that SeTal prevents endothelial dysfunction by scavenging reactive oxidants in isolated mouse aorta under conditions of acute oxidative stress induced by hyperglycaemia. Aortae were isolated from C57BL/6 male mice and mounted on a wire-myograph to assess vascular function. In the presence of a superoxide radical generator, pyrogallol, 300μM and 1mM of SeTal effectively prevented endothelial dysfunction compared to other selenium-containing compounds. In a second set of ex vivo experiments, mouse aortae were incubated for three days with either normal or high glucose, and co-incubated with SeTal at 37°C in 5% CO 2 . High glucose significantly reduced the sensitivity to the endothelium-dependent agonist, acetylcholine (ACh), increased superoxide production and decreased basal nitric oxide (NO) availability. SeTal (1mM) co-treatment prevented high glucose-induced endothelial dysfunction and oxidative stress in the mouse aorta. The presence of a cyclooxygenase inhibitor, indomethacin significantly improved the sensitivity to ACh in high glucose-treated aortae, but had no effect in SeTal-treated aortae. Our data show that SeTal has potent antioxidant activity in isolated mouse aortae and prevents high glucose-induced endothelial dysfunction by decreasing superoxide levels, increasing basal NO availability and normalising the contribution of vasoconstrictor prostanoids., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Disulfide bonds play a key role in stabilizing protein structures, with disruption strongly associated with loss of protein function and activity. Previous data have suggested that disulfides show only modest reactivity with oxidants. In the current study, we report kinetic data indicating that selected disulfides react extremely rapidly, with a variation of 10 4 in rate constants. Five-membered ring disulfides are particularly reactive compared with acyclic (linear) disulfides or six-membered rings. Particular disulfides in proteins also show enhanced reactivity. This variation occurs with multiple oxidants and is shown to arise from favorable electrostatic stabilization of the incipient positive charge on the sulfur reaction center by remote groups, or by the neighboring sulfur for conformations in which the orbitals are suitably aligned. Controlling these factors should allow the design of efficient scavengers and high-stability proteins. These data are consistent with selective oxidative damage to particular disulfides, including those in some proteins.

α-Bromo aluminium acetals are suitable substrates for Ueno-Stork-like radical cyclisations affording γ-lactols and acid-sensitive methylene-γ-lactols in high yields. The mechanistic study herein sets the scope and limitation of this reaction. The influence of the halide (or chalcogenide) atom X (X=Cl, Br, I, SPh, SePh) in the precursors α-haloesters, as well as influence of the solvent and temperature was studied. The structure of the aluminium acetal intermediates resulting from the reduction of the corresponding α-haloesters has been investigated by low-temperature (13) C-INEPT diffusion-ordered NMR spectroscopy (DOSY) experiments and quantum calculations, providing new insights into the structures of these thermally labile intermediates. Oxygen-bridged dimeric structures with a planar Al2 O2 ring are proposed for the least hindered aluminium acetals, while monomeric structures seem to prevail for the most hindered species. A comparison against the radical cyclisation of aluminium acetals derived from allyl and propargyl alcohols with the parent Ueno-Stork has been made at the BHandHLYP/6-311++G(d,p) level of theory, highlighting mechanistic similarities and differences., (© 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Two novel cell-permeable and bacteria-compatible 'turn-on' fluorescent probes, designed to be compatible in a multi-dye system and to fluoresce in the blue region exhibiting emission maxima of 440-490 nm, were synthesized. The profluorescent nitroxide probe (11) was developed to visualize and quantify free radical and redox processes, and the Cu(II)-complexed coumarin-based probe (16a) was developed for NO detection. Confocal laser-scanning microscopy and subsequent digital analysis of Pseudomonas aeruginosa biofilms stained with 11 or 16a determined that free radical and redox processes and NO generation occur predominantly in live cells during normal biofilm growth.

Peroxynitrite (the physiological mixture of ONOOH and its anion, ONOO(-)) is a powerful biologically-relevant oxidant capable of oxidizing and damaging a range of important targets including sulfides, thiols, lipids, proteins, carbohydrates and nucleic acids. Excessive production of peroxynitrite is associated with several human pathologies including cardiovascular disease, ischemic-reperfusion injury, circulatory shock, inflammation and neurodegeneration. This study demonstrates that low-molecular-mass selenols (RSeH), selenides (RSeR') and to a lesser extent diselenides (RSeSeR') react with peroxynitrite with high rate constants. Low molecular mass selenols react particularly rapidly with peroxynitrite, with second order rate constants k2 in the range 5.1 × 10(5)-1.9 × 10(6)M(-1)s(-1), and 250-830 fold faster than the corresponding thiols (RSH) and many other endogenous biological targets. Reactions of peroxynitrite with selenides, including selenosugars are approximately 15-fold faster than their sulfur homologs with k2 approximately 2.5 × 10(3)M(-1)s(-1). The rate constants for diselenides and sulfides were slower with k2 0.72-1.3 × 10(3)M(-1)s(-1) and approximately 2.1 × 10(2)M(-1)s(-1) respectively. These studies demonstrate that both endogenous and exogenous selenium-containing compounds may modulate peroxynitrite-mediated damage at sites of acute and chronic inflammation, with this being of particular relevance at extracellular sites where the thiol pool is limited., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Hypochlorous acid (HOCl) and N-chloramines are produced by myeloperoxidase (MPO) as part of the immune response to destroy invading pathogens. However, MPO also plays a detrimental role in inflammatory pathologies, including atherosclerosis, as inappropriate production of oxidants, including HOCl and N-chloramines, causes damage to host tissue. Low molecular mass thiol compounds, including glutathione (GSH) and methionine (Met), have demonstrated efficacy in scavenging MPO-derived oxidants, which prevents oxidative damage in vitro and ex vivo. Selenium species typically have greater reactivity toward oxidants compared to the analogous sulfur compounds, and are known to be efficient scavengers of HOCl and other hypohalous acids produced by MPO. In this study, we examined the efficacy of a number of sulfur and selenium compounds to scavenge a range of biologically relevant N-chloramines and oxidants produced by both isolated MPO and activated neutrophils and characterized the resulting selenium-derived oxidation products in each case. A dose-dependent decrease in the concentration of each N-chloramine was observed on addition of the sulfur compounds (cysteine, methionine) and selenium compounds (selenomethionine, methylselenocysteine, 1,4-anhydro-4-seleno-L-talitol, 1,5-anhydro-5-selenogulitol) studied. In general, selenomethionine was the most reactive with N-chloramines (k2 0.8-3.4×10(3)M(-1) s(-1)) with 1,5-anhydro-5-selenogulitol and 1,4-anhydro-4-seleno-L-talitol (k2 1.1-6.8×10(2)M(-1) s(-1)) showing lower reactivity. This resulted in the formation of the respective selenoxides as the primary oxidation products. The selenium compounds demonstrated greater ability to remove protein N-chloramines compared to the analogous sulfur compounds. These reactions may have implications for preventing cellular damage in vivo, particularly under chronic inflammatory conditions., (Copyright © 2015 Elsevier Inc. All rights reserved.)

A series of 23 nitroxides () was tested for biofilm modulatory activity using a crystal violet staining technique. 3-(Dodecane-1-thiyl)-4-(hydroxymethyl)-2,2,5,5-tetramethyl-1-pyrrolinoxyl () was found to significantly suppress biofilm formation and elicit dispersal events in both Pseudomonas aeruginosa and mixed-culture biofilms. Twitching and swarming motilities were enhanced by nitroxide , leaving the planktonic-specific swimming motility unaffected and suggesting that the mechanism of -mediated biofilm modulation is linked to the hyperactivation of surface-associated cell motilities. Preliminary structure-activity relationship studies identify the dodecanethiyl chain, hydroxymethyl substituent and the free radical moiety to be structural features pertinent to the anti-biofilm activity of .

Competition kinetic studies augmented with laser-flash photolysis and high-level computational techniques [G3(MP2)-RAD], with [COSMO-RS, SMD] and without solvent correction, provide kinetic parameters for the ring closures of a series of 4-(alkylseleno)butyl radicals 1. At 22 °C rate constants (kc) that lie between 10(4)-10(7) s(-1) were determined experimentally and correlate with expectations based on leaving group ability. Activation energies (Eact) were determined to lie between 10.6 (R = Ph2CH) and 28.0 (R = n-Bu) kJ mol(-1), while log(A/s(-1)) values were generally between 9 and 10 in benzene. Computationally determined rate constants were in good-to-excellent agreement with those determined experimentally, with the COSMO-RS solvation model providing values that more closely resemble those from experiment than SMD.

3-(Dodecanethiyl)-4-(hydroxymethyl)-2,2,5,5-tetramethyl-1-pyrrolinoxyl (5) effectively disperses biofilms of relevance to cultural materials while preventing their formation.

N,S-Dimethyldithiocarbamyl oxalates (e.g.6, 10) are novel, readily prepared precursors to alkyloxyacyl radicals 1 that are more suitable for kinetic studies than existing precursors; 10 has allowed the determination of accurate rate data for the cyclization of the butenyloxyacyl radical 5 (kc = 1.2 × 10(7) s(-1) at 21 °C).

Free radicals and oxidative stress play important roles in the deterioration of materials, and free radicals are important intermediates in many biological processes. The ability to detect these reactive species is a key step on the road to their understanding and ultimate control. This short review highlights recent progress in the development of reagents for the detection of free radicals and reactive oxygen species with broad application to materials science as well as biology.

In this viewpoint article we reflect on the state of play of organic free radical chemistry before the contributions of Beckwith et al. to our understanding of the factors that control intramolecular homolytic addition chemistry, and the rapid rise in the use of this chemistry once the impact of the "guidelines for radical reactions" became fully appreciated.

Due to their stability, availability and reactivity, sulfides are particularly attractive sources of carbon-centered radicals. However, their reactivity in homolytic substitution processes is strongly reduced when compared with the corresponding selenides or halides. Despite this, sulfur-containing compounds can be engineered so that they become effective agents in radical chain reactions. A detailed description of the reactivity of organo-sulfur compounds is reported here with the aim of providing clear guidance on the scope and limitation of their use as radical precursors in chain reactions.

Generation of the 5-(2'-deoxyuridinyl)methyl radical (6) was reexamined. Trapping by 4-hydroxy-2,2,6,6-tetramethylpiperidin-1-oxyl confirms that 6 is generated. However, trapping by methoxyamine reveals that the respective carbocation (10) is also produced. Examining the effects of these traps on products in DNA reveals that the carbocation and not 6 yields interstrand cross-links. Cross-link formation from the carbocation is consistent with DFT calculations that predict that addition at the N1 position of dA is essentially barrierless.

Aryl hydrazides are oxidised to acyl radicals through a mechanism involving diimide intermediates that are prone to nucleophilic acyl substitution. This oxidation occurs regardless of the oxidant involved, however there is no evidence that the acyl radical formed undergoes further oxidation to the corresponding acylium ion, even in the presence of strong oxidants. This study may provide insight into the mechanism of isoniazid resistance in Mycobacterium tuberculosis.

Heme peroxidases including myeloperoxidase (MPO) are released at sites of inflammation by activated leukocytes. MPO generates hypohalous acids (HOX, X = Cl, Br, SCN) from H(2)O(2); these oxidants are bactericidal and are key components of the inflammatory response. However, excessive, misplaced or mistimed production can result in host tissue damage, with this implicated in multiple inflammatory diseases. We report here methods for the conversion of simple monosaccharide sugars into selenium- and sulfur-containing species that may act as potent water-soluble scavengers of HOX. Competition kinetic studies show that the seleno species react with HOCl with rate constants in the range 0.8-1.0 × 10(8) M(-1) s(-1), only marginally slower than those for the most susceptible biological targets including the endogenous antioxidant, glutathione. The rate constants for the corresponding sulfur-sugars are considerably slower (1.4-1.9 × 10(6) M(-1) s(-1)). Rate constants for reaction of the seleno-sugars with HOBr are ~8 times lower than those for HOCl (1.0-1.5 × 10(7) M(-1) s(-1)). These values show little variation with differing sugar structures. Reaction with HOSCN is slower (~10(2) M(-1) s(-1)). The seleno-sugars decreased the extent of HOCl-mediated oxidation of Met, His, Trp, Lys, and Tyr residues, and 3-chlorotyrosine formation, on both isolated bovine serum albumin and human plasma proteins, at concentrations as low as 50 μM. These studies demonstrate that novel selenium (and to a lesser extent, sulfur) derivatives of monosaccharides could be potent modulators of peroxidase-mediated damage at sites of acute and chronic inflammation, and in multiple human pathologies.

In this study we have investigated the in vitro angiotensin II receptor antagonist and antioxidant activity of a series of compounds in which the antioxidant pharmacophores (selenium, phenol, benzothiophene, ebselen or nitroxide) have been incorporated into the AT(1) receptor antagonist (sartan) milfasartan. Activity of these compounds was assessed in tissue-based assays. The novel molecules (30nM), nitrasartan or phenol-milfasartan, retained AT(1) receptor antagonist potency in rat isolated right atria. Antioxidant capacity of the substituted sartans was examined in an AAPH (2,2'-azobis (2-amidinopropane) hydrochloride)-induced haemolysis assay (mouse C57/BL6 isolated erythrocytes). Each of the antioxidant pharmacophores (10μM), except benzothiophene, protected against radical-mediated lysis. Of the novel sartans, only analogues incorporating selenium, phenol or nitroxide (nitrasartan) protected against radical-induced haemolysis. In the tissue-based assay using mouse isolated paced left atria, the free radical generator doxorubicin (30μM) resulted in a decrease in left atrial force over 90min. In this assay the phenol, nitroxide or ebselen antioxidant pharmacophores protected against doxorubicin-induced negative inotropy but selenocystine and benzothiophene did not. Nitrasartan (10μM) was the only novel analogue to protect against radical-induced negative inotropy. Nitrasartan also antagonised angiotensin II responses and decreased superoxide production in a concentration-dependent manner in rat isolated carotid arteries and aortae, respectively. In conclusion, nitrasartan is a dual action molecule demonstrating both AT(1) receptor antagonist potency and antioxidant properties in vitro., (Copyright © 2012 Elsevier B.V. All rights reserved.)

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.

High level calculations suggest that homolytic substitution (S(H)2) by alkyl radicals at sulfur proceeds through a mechanism that is assisted and dominated by LP → SOMO interactions; in the absence of these interactions, S(H)2 chemistry at sulfur is predicted to be virtually impossible. G3(MP2)-RAD calculations suggest that cyclization of the tert-butylsulfonylbutyl radical 2 (n = 2) proceeds with a rate constant of 1.7 × 10(-24) s(-1) at 80°, some 28 orders of magnitude slower than its sulfide cousin (n = 0).

Novel paramagnetic selective angiotensin AT(1) receptor antagonists (sartans) bearing nitroxides (3, 4) have been prepared and their pharmacology evaluated in vitro as well as in vivo. Compounds 3, 4 proved to be effective sartans with pK(B) estimates in the range 6.2-9.1. In addition, the sodium salt (11) of 4 (R = Bu) is able to protect against vascular injury in hypertensive rats as determined by its ability to attenuate the development of intimal thickening caused by balloon injury of the carotid artery.

To take advantage of the full potential of functionalized transition metal oxides, a well-understood nonsilane based grafting technique is required. The functionalization of mixed titanium zirconium oxides was studied in detail using a bisphosphonic acid, featuring two phosphonic acid groups with high surface affinity. The bisphosphonic acid employed was coupled to a UV active benzamide moiety in order to track the progress of the surface functionalization in situ. Using different material compositions, altering the pH environment, and looking at various annealing conditions, key features of the functionalization process were identified that consequently will allow for intelligent material design. Loading with bisphosphonic acid was highest on supports calcined at 650 °C compared to lower calcination temperatures: A maximum capacity of 0.13 mmol g(-1) was obtained and the adsorption process could be modeled with a pseudo-second-order rate relationship. Heating at 650 °C resulted in a phase transition of the mixed binary oxide to a ternary oxide, titanium zirconium oxide in the srilankite phase. This phase transition was crucial in order to achieve high loading of the bisphosphonic acid and enhanced chemical stability in highly acidic solutions. Due to the inert nature of phosphorus-oxygen-metal bonds, materials functionalized by bisphosphonic acids showed increased chemical stability compared to their nonfunctionalized counterparts in harshly acidic solutions. Leaching studies showed that the acid stability of the functionalized material was improved with a partially crystalline srilankite phase. The materials were characterized using nitrogen sorption, X-ray powder diffraction, and UV-vis spectroscopy; X-ray photoelectron spectroscopy was used to study surface coverage with the bisphosphonic acid molecules.

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., (This journal is © The Royal Society of Chemistry 2011)

Ab initio and density functional theory (DFT) calculations predict that intramolecular homolytic substitution by alkyl radicals at the sulfur atom in sulfinates proceeds through a smooth transition state in which the attacking and leaving radicals adopt a near collinear arrangement. When forming a five-membered ring and the leaving radical is methyl, G3(MP2)-RAD//ROBHandHLYP/6-311++G(d,p) calculations predict that this reaction proceeds with an activation energy (ΔE(1)(‡)) of 43.2 kJ mol(-1). ROBHandHLYP/6-311++G(d,p) calculations suggest that the formation of five-membered rings through intramolecular homolytic substitution by aryl radicals at the sulfur atom in sulfinates and sulfinamides, with expulsion of phenyl radicals, proceeds with the involvement of hypervalent intermediates. These intermediates further dissociate to the observed products, with overall energy barriers of 45-68 kJ mol(-1), depending on the system of interest. In each case, homolytic addition to the phenyl group competes with substitution, with calculated barriers of 51-78 kJ mol(-1). This computational study complements and provides insight into previous experimental observations.

Ab initio and DFT calculations reveal that both imidoyl and thioyl radicals add to the nitrogen end of methanimine through simultaneous SOMO-π*(imine), SOMO-π(imine), SOMO-LP(N) and π*(radical)-LP(N) interactions between the radical and the imine. At the CCSD(T)/cc-pVDZ//BHandHLYP/cc-pVTZ level of theory, barriers of 13.8 and 26.1 kJ mol(-1) are calculated for the attack of the methylimidoyl radical at the carbon- and nitrogen- end of methanimine, respectively, indicating that the imidoyl radial has a preference for addition to the nitrogen end of imine. On the other hand, barriers of 25.1 and 13.4 kJ mol(-1) are calculated at the same level of theory for the addition reaction of the methanethioyl radical at the carbon- and nitrogen- end of methanimine, respectively. Natural bond orbital (NBO) analysis at the BHandHLYP/6-311G** level of theory reveals that SOMO-π*(imine), SOMO-π(imine), SOMO-LP(N) and π*(radical)-LP(N) interactions are worth 111, 89, 115 and 17 kJ mol(-1), respectively, in the transition state (4) for the reaction of methylimidoyl radical at the nitrogen end of methanimine; similar interactions are observed for the chemistry involving all the radicals studied here. These multi-component interactions are responsible for the unusual motion vectors associated with the transition states involved in these reactions.

Rate constant data and Arrhenius parameters have been determined for a series of substituted hexenyl radicals of differing electronic and steric demand. Electron-withdrawing groups (CF(3), CO(2)Et) directly attached to the radical centre slightly accelerate 5-exo ring-closure (k(cis) + k(trans) ∼ 2.1 × 10(5) s(-1) at 25°) relative to donating groups (OMe; 1.6 × 10(5) s(-1) at 25°). Sterically demanding groups (tert-Bu), as expected, slow the cyclization process (1 × 10(5) s(-1)). These observations are consistent with subtle changes in activation energy for 5-exo ring-closure. Interestingly, the nature of the solvent would appear to have a significant influence on this chemistry with the cis/trans stereoselectivity sometimes improved as the solvent polarity is increased. Except for the system containing the CF(3) (electron-withdrawing) group which displays an increase in the cyclization/capture rate constant (k(c)/k(H)), a general decrease in the k(c)/k(H) ratio as solvent polarity is increased is noted; these changes have been speculated to arise mainly from changes in k(H) in the various solvents employed.

Benzothiophene and benzoselenophene analogues of the thiophene-containing antihypertensives milfasartan and eprosartan were prepared and tested for AT(1) receptor antagonist properties. While the sulfur-containing systems were prepared following existing methodology, the selenium-containing analogues required the development of novel, tandem free-radical chemistry involving addition of aryl radicals to alkynes, followed by intramolecular homolytic substitution at the higher heteroatom. All four compounds prepared proved to be excellent AT(1) receptor antagonists, with pK(B) estimates of 7.2-9.5.

Competitive kinetic experiments utilising free radical carbonylation chemistry provide a first estimate for the rate constant for 6-endo cyclization of the 6-aza-7-ethyl-5-hexenoyl radical of (4.8 +/- 2.4) x 10(6) s(-1) at 90 degrees C in benzene, in good agreement with ONIOM-G3(MP2)-CC+COSMO-RS calculations (6.8 x 10(6) s(-1)).

Mechanistic investigations on the previously reported reduction of B-alkylcatecholboranes in the presence of methanol led to the disclosure of a new mechanism involving catechol as a reducing agent. More than just revising the mechanism of this reaction, we disclose here the surprising role of catechol, a chain breaking antioxidant, which becomes a source of hydrogen atoms in an efficient radical chain process.

Selenochromanes and analogues are conveniently prepared through a tandem homolytic addition/substitution sequence involving suitably substituted olefins.