Inhibition of myeloperoxidase- and neutrophil-mediated oxidant production by tetraethyl and tetramethyl nitroxides

The powerful oxidant HOCl (hypochlorous acid and its corresponding anion, −OCl) generated by the myeloperoxidase (MPO)–H2O2–Cl− system of activated leukocytes is strongly associated with multiple human inflammatory diseases; consequently there is considerable interest in inhibition of this enzyme. Nitroxides are established antioxidants of low toxicity that can attenuate oxidation in animal models, with this ascribed to superoxide dismutase or radical-scavenging activities. We have shown (M.D. Rees et al., Biochem. J. 421, 79–86, 2009) that nitroxides, including 4-amino-TEMPO (4-amino-2,2,6,6-tetramethylpiperidin-1-yloxyl radical), are potent inhibitors of HOCl formation by isolated MPO and activated neutrophils, with IC50 values of ~1 and ~6 µM respectively. The utility of tetramethyl-substituted nitroxides is, however, limited by their rapid reduction by biological reductants. The corresponding tetraethyl-substituted nitroxides have, however, been reported to be less susceptible to reduction. In this study we show that the tetraethyl species were reduced less rapidly than the tetramethyl species by both human plasma (89–99% decreased rate of reduction) and activated human neutrophils (62–75% decreased rate). The tetraethyl-substituted nitroxides retained their ability to inhibit HOCl production by MPO and activated neutrophils with IC50 values in the low-micromolar range; in some cases inhibition was enhanced compared to tetramethyl substitution. Nitroxides with rigid structures (fused oxaspiro rings) were, however, inactive. Overall, these data indicate that tetraethyl-substituted nitroxides are potent inhibitors of oxidant formation by MPO, with longer plasma and cellular half-lives compared to the tetramethyl species, potentially allowing lower doses to be employed.

Unimolecular reaction chemistry of a charge-tagged beta-hydroxyperoxyl radical

β-Hydroxyperoxyl radicals are formed during atmospheric oxidation of unsaturated volatile organic compounds such as isoprene. They are intermediates in the combustion of alcohols. In these environments the unimolecular isomerization and decomposition of β-hydroxyperoxyl radicals may be of importance, either through chemical or thermal activation. We have used ion-trap mass spectrometry to generate the distonic charge-tagged β-hydroxyalkyl radical anion, ˙CH2C(OH)(CH3)CH2C(O)O−, and investigated its subsequent reaction with O2 in the gas phase under conditions that are devoid of complicating radical–radical reactions. Quantum chemical calculations and master equation/RRKM theory modeling are used to rationalize the results and discern a reaction mechanism. Reaction is found to proceed via initial hydrogen abstraction from the γ-methylene group and from the β-hydroxyl group, with both reaction channels eventually forming isobaric product ions due to loss of either ˙OH + HCHO or ˙OH + CO2. Isotope labeling studies confirm that a 1,5-hydrogen shift from the β-hydroxyl functionality results in a hydroperoxyalkoxyl radical intermediate that can undergo further unimolecular dissociations. Furthermore, this study confirms that the facile decomposition of β-hydroxyperoxyl radicals can yield ˙OH in the gas phase.

A New Tetrahydrofurannulation Via Tandem Radical Cyclization Reaction-Reductive Deoxygenation Sequence

Treatment of bromoketals 2, derived from allyl alcohols 1, with tributyltin chloride, sodium cyanoborohydride and AIBN furnishes the tetrahydrofurannulated products 3 via a 5-exo-trig radical cyclisation reaction followed by reductive cleavage of ketal 4.

Time-Resolved Resonance Raman Spectroscopic Studies on the Radical Anions of Menaquinone and Naphthoquinone

Quinones and their radical ion intermediates have been much studied by vibrational spectroscopy to understand their structure-function relationships in various biological processes. In this paper, we present a comprehensive analysis of vibrational spectra in the structure-sensitive region of both the naphthoquinone (NQ) and 2-methyl-1,4-naphthoquinone (MQ, menaquinone) radical anions using time-resolved resonance Raman and ab initio studies. Specific vibrational mode assignments have been made to all the vibrational frequencies recorded in the experiment. It is observed that the carbonyl and C-C stretching frequencies show considerable coupling in NQ and MQ radical anions. Further, the asymmetric substitution present in MQ with respect to NQ shows important signatures in the radical anion spectrum. It is concluded that assignments of vibrational frequencies of asymmetrically substituted quinones must take into consideration the influence of asymmetry on structure and reactivity.

Formal total synthesis of 2-pupukeanone via radical mediated cyclisation of an enyne

Diels-Alder reaction of the dienone 12, obtained by C-alkylation of sodium 2,6-dimethylphenoxide, with acrylonitrile and phenyl vinyl sulfones generate the enynes 14 and 17. Tributyltin radical addition to the terminal acetylene in 14 and 17 lead to the vinylstannanes 15 and 18 via 5-exo trig cyclisation of the resulting vinyl radical, which on oxidative cleavage furnishes the isotwistane-diones 16 and 19. Reductive desulfonylation of the diketosulfone 19 furnishes the dione 11, constituting a formal total synthesis of 2-pupukeanone 5 and 2-isocyanopupukeanone 3.

Bridged systems via radical cyclization reactions. Stereospecific synthesis of chiral tricyclo[6.2.1.0(1,5)]undecanes

The application of radical-mediated cyclizations and annulations in organic synthesis has grown in importance steadily over the years to reach the present status where they are now routinely used in the strategy-level planning.2 The presence of a quaternary carbon atom is frequently encountered in terpenoid natural products, and it often creates a synthetic challenge when two or more quaternary carbon atoms are present in a contiguous manner.3 Even though creation of a quaternary carbon atom by employing a tertiary radical is very facile, creation of a quaternary carbon atom (or a spiro carbon atom) via radical addition onto a fully substituted olefinic carbon atom is not that common but of synthetic importance. For example, the primary radical derived from the bromide 1 failed to cyclize to generate the two vicinal quaternary carbon atoms and resulted in only the reduced product 2.4 The tricyclic carbon framework tricyclo[6.2.1.01,5]undecane (3) is present in a number of sesquiterpenoids e.g. zizzanes, prelacinanes, etc.5

Requirement Of A Diperoxovanadate-Derived Intermediate for the Interdependent Oxidation Of Vanadyl And Nadh

Oxygen release accompanying oxidation of vanadyl by diperoxovanadate was suppressed on addition of NADH. The added NADH was rapidly oxidized, oxygen in the medium was consumed, and the reaction terminated on exhaustion of either NADH or vanadyl. The consumption of oxygen and disappearance of NADH needed small concentrations of diperoxovanadate to initiate and increased with increase in the concentration of vanadyl and NADH or decrease of pH. The products of the reaction were found to be NAD(+) from NADH and vanadate oligomers from vanadyl and oxygen. The reaction was insensitive to catalase and was not dependent on H2O2. The reaction was inhibited by superoxide dismutase, cytochrome c, EDTA, Mn2+, histidine, and DMPO, but not by hydroxyl radical scavengers such as ethanol and benzoate, The ESR spectrum of the reaction mixture showed the presence of the 1:2:2:1 quartet signal typical of a DMPO-OH adduct, but this was not modified by ethanol, This oxygen radical species, possibly of (OV)-O-. type derived from diperoxovanadate, is proposed to have a role in the reactions of oxygen release and NADH oxidation

Kinetic analysis of nitroxide radical coupling reactions mediated by CuBr

In a previous paper, we described the room temperature rapid, selective, reversible, and near quantitative Cu-activated nitroxide radical coupling (NRC) technique to prepare 3-arm polystyrene stars. In this work, we evaluated the Cu-activation mechanism, either conventional atom transfer or single electron transfer (SET), through kinetic simulations. Simulation data showed that one can describe the system by either activation mechanism. We also found through simulations that bimolecular radical termination, regardless of activation mechanism, was extremely low and could be considered negligible in an NRC reaction. Experiments were carried out to form 2- and 3-arm PSTY stars using two ligands, PMDETA and Me6TREN, in a range of solvent conditions by varying the ratio of DMSO to toluene, and over a wide temperature range. The rate of 2- or 3-arm star formation was governed by the choice of solvent and ligand. The combination of Me6TREN and toluene/DMSO showed a relatively temperature independent rate, and remarkably reached near quantitative yields for 2-arm star formation after only 1 min at 25 °C.

Ultrafast and reversible multiblock formation by the SET-Nitroxide radical coupling reaction

The single electron transfer-nitroxide radical coupling (SET-NRC) reaction has been used to produce multiblock polymers with high molecular weights in under 3 min at 50◦C by coupling a difunctional telechelic polystyrene (Br-PSTY-Br)with a dinitroxide. The well known combination of dimethyl sulfoxide as solvent and Me6TREN as ligand facilitated the in situ disproportionation of CuIBr to the highly active nascent Cu0 species. This SET reaction allowed polymeric radicals to be rapidly formed from their corresponding halide end-groups. Trapping of these carbon-centred radicals at close to diffusion controlled rates by dinitroxides resulted in high-molecular-weight multiblock polymers. Our results showed that the disproportionation of CuI was critical in obtaining these ultrafast reactions, and confirmed that activation was primarily through Cu0. We took advantage of the reversibility of the NRC reaction at elevated temperatures to decouple the multiblock back to the original PSTY building block through capping the chain-ends with mono-functional nitroxides. These alkoxyamine end-groups were further exchanged with an alkyne mono-functional nitroxide (TEMPO–≡) and ‘clicked’ by a CuI-catalyzed azide/alkyne cycloaddition (CuAAC) reaction with N3–PSTY–N3 to reform the multiblocks. This final ‘click’ reaction, even after the consecutive decoupling and nitroxide-exchange reactions, still produced high molecular-weight multiblocks efficiently. These SET-NRC reactions would have ideal applications in re-usable plastics and possibly as self-healing materials.

Rapid, selective, and reversible Nitroxide Radical Coupling (NRC) reactions at amibient temperature

High activation of polystyrene with bromine end groups (PSTY-Br) to their incipient radicals occurred in the presence of Cu(I)Br, Me6TREN, and DMSO solvent. These radicals were then trapped by nitroxide species leading to coupling reactions between PSTY-Br and nitroxides that were ultrafast and selective in the presence of a diverse range of functional groups. The nitroxide radical coupling (NRC) reactions have the attributes of a “click” reaction with near quantitative yields of product formed, but through the reversibility of this reaction, it has the added advantage of permitting the exchange of chemical functionality on macromolecules. Conditions were chosen to facilitate the disproportionation of Cu(I)Br to the highly activating nascent Cu(0) and deactivating Cu(II)Br2 in the presence of DMSO solvent and Me6TREN ligand. NRC at room temperature gave near quantitative yields of macromolecular coupling of low molecular weight polystyrene with bromine chain-ends (PSTY-Br) and nitroxides in under 7 min even in the presence of functional groups (e.g., −≡, −OH, −COOH, −NH2, =O). Utilization of the reversibility of the NRC reaction at elevated temperatures allowed the exchange of chain-end groups with a variety of functional nitroxide derivatives. The robustness and orthogonality of this NRC reaction were further demonstrated using the Cu-catalyzed azide/alkyne “click” (CuAAC) reactions, in which yields greater than 95% were observed for coupling between PSTY-N3 and a PSTY chain first trapped with an alkyne functional TEMPO (PSTY-TEMPO-≡).

Radical nursing and the emergence of technique as healthcare technology

The integration of technology in care is core business in nursing and this role requires that we must understand and use technology informed by evidence that goes much deeper and broader than actions and behaviours. We need to delve more deeply into its complexity because there is nothing minor or insignificant about technology as a major influence in healthcare outcomes and experiences. Evidence is needed that addresses technology and nursing from perspectives that examine the effects of technology, especially related to increasing demands for efficiency, the relationship of technology to nursing and caring, and a range of philosophical questions associated with empowering people in their healthcare choices. Specifically, there is a need to confront in practice the ways technique influences care. Technique is the creation of a kind of thinking that is necessary for contemporary healthcare technology to develop and be applied in an efficient and rational manner. Technique is not an entity or specific thing, but rather a way of thinking that seeks to shape and organize nursing activity, and manage efficiently individual difference(s) in care. It emphasizes predetermined causal relationships, conformity, and sameness of product, process, and thought. In response is needed a radical vision of nursing that attempts in a real sense to ensure we meet the needs of individuals and their community. Activism and advocacy are needed, and a willingness to create a certain detachment from the imperatives that technique demands. It is argued that our responsibility as nurses is to respond in practice to the errors, advantages, difficulties, and temptations of technology for the benefit of those who most need our assistance and care.

A Radical Cyclization Route To +/-Andirolactone, A Spiro-Gamma-Butyrolactone

Synthesis of Andirolactone (Image ), starting from 4-methyl cyclohex-3-en-1-one (Image ), via the radical cyclisation of the bromoacetal (Image ), is described.

Radical Enhanced Atomic Layer Deposition of Metals and Oxides

Atomic Layer Deposition (ALD) is a chemical, gas-phase thin film deposition method. It is known for its ability for accurate and precise thickness control, and uniform and conformal film growth. One area where ALD has not yet excelled is film deposition at low temperatures. Also deposition of metals, besides the noble metals, has proven to be quite challenging. To alleviate these limitations, more aggressive reactants are required. One such group of reactants are radicals, which may be formed by dissociating gases. Dissociation is most conveniently done with a plasma source. For example, dissociating molecular oxygen or hydrogen, oxygen or hydrogen radicals are generated. The use of radicals in ALD may surmount some of the above limitations: oxide film deposition at low temperatures may become feasible if oxygen radicals are used as they are highly reactive. Also, as hydrogen radicals are very effective reducing agents, they may be used to deposit metals. In this work, a plasma source was incorporated in an existing ALD reactor for radical generation, and the reactor was used to study five different Radical Enhanced ALD processes. The modifications to the existing reactor and the different possibilities during the modification process are discussed. The studied materials include two metals, copper and silver, and three oxides, aluminium oxide, titanium dioxide and tantalum oxide. The materials were characterized and their properties were compared to other variations of the same process, utilizing the same metal precursor, to understand what kind of effect the non-metal precursor has on the film properties and growth characteristics. Both metals were deposited successfully, and silver for the first time by ALD. The films had low resistivity and grew conformally in the ALD mode, demonstrating that the REALD of metals is true ALD. The oxide films had exceptionally high growth rates, and aluminium oxide grew at room temperature with low cycle times and resulted in good quality films. Both aluminium oxide and titanium dioxide were deposited on natural fibres without damaging the fibre. Tantalum oxide was also deposited successfully, with good electrical properties, but at slightly higher temperature than the other two oxides, due to the evaporation temperature required by the metal precursor. Overall, the ability of REALD to deposit metallic and oxide films with high quality at low temperatures was demonstrated.

The radical in arts education research

Arts education research, as an interdisciplinary field, has developed in the shadows of a number of research traditions. However amid all the methodological innovation, I believe there is one particular, distinctive and radical research strategy which arts educators have created to research the practice of arts education: namely arts-based research. For many, and Elliot Eisner from Stanford University was among the first, arts education needed a research approach which could deal with the complex dynamics of arts education in the classroom. What was needed was ‘an approach to the conduct of educational research that was rooted in the arts and that used aesthetically crafted forms to reveal aspects of practice that mattered educationally’ (Eisner 2006: 11). While arts education researchers were crafting the principles and practices of arts-based research, fellow artist/researchers in the creative arts were addressing similar needs and fashioning their own exacting research strategies. This chapter aligns arts-based research with the complementary research practices established in creative arts studios and identifies the shared and truly radical nature of these moves. Finally, and in a contemporary turn many will find surprising, I will discuss how the radical aspects of these methodologies are now being held up as core elements of what is being called the fourth paradigm of scientific research, known as eScience. Could it be that the radical dynamics of arts-based research pre-figured the needs of eScience researchers who are currently struggling to manage the ‘deluge of Big Data’ which is disrupting their well-established scientific methods?