Mono-oxygen Species Research Articles

Further Insights into the Oxidative Pathway of Thiocarbonyl-Type Antitubercular Prodrugs: Ethionamide, Thioacetazone, and Isoxyl.

A chemical activation study of the thiocarbonyl-type antitubercular prodrugs, ethionamide (ETH), thioacetazone (TAZ), and isoxyl (ISO), was performed. Biomimetic oxidation of ethionamide using H2O2 (1 equiv) led to ETH-SO as the only stable S-oxide compound, which was found to occur in solution in the preferential form of a sulfine (ETH═S═O vs the sulfenic acid tautomer ETH-S-OH), as previously observed in the crystal state. It was also demonstrated that ETH-SO is capable of reacting with amines, as the putative sulfinic derivative (ETH-SO2H) was supposed to do. Unlike ETH, oxidation of TAZ did not allow observation of the mono-oxygenated species (TAZ-SO), leading directly to the more stable sulfinic acid derivative (TAZ-SO2H), which can then lose a SOxH group after further oxidation or when placed in a basic medium. It was also noticed that the unstable TAZ-SO intermediate can lead to the carbodiimide derivative as another electrophilic species. It is suggested that TAZ-SOH, TAZ-SO2H, and the carbodiimide compound can also react with NH2-containing nucleophilic species, and therefore be involved in toxic effects. Finally, ISO showed a very complex reactivity, here assigned to the coexistence of two mono-oxygenated structures, the sulfine and sulfenic acid tautomers. The mono- and dioxygenated derivatives of ISO are also highly unstable, leading to a panel of multiple metabolites, which are still reactive and likely contribute to the toxicity of this prodrug.

LA-ICP-MS/MS improves limits of detection in elemental bioimaging of gadolinium deposition originating from MRI contrast agents in skin and brain tissues

A novel analytical method to detect the retention of gadolinium from contrast agents for magnetic resonance imaging (MRI) in tissue samples of patients is presented. It is based on laser ablation - inductively coupled plasma - triple quadrupole - mass spectrometry (LA-ICP-MS/MS). Both Gd and P were monitored with a mass shift of +16, corresponding to mono-oxygenated species, as well as Zn, Ca, and Fe on-mass. This method resulted in a significantly reduced background and improved limits of detection not only for phosphorus, but also for gadolinium. These improvements were essential to perform elemental bioimaging with improved resolution of 5 μm x 5 μm, allowing the detection of small Gd deposits in fibrotic skin and brain tumour tissue with diameters of approximately 50 μm. Detailed analyses of these regions revealed that most Gd was accompanied with P and Ca, indicating co-precipitation.

Identification of selected in vitro generated phase-I metabolites of the steroidal selective androgen receptor modulator MK-0773 for doping control purposes.

Research into developing anabolic agents for various therapeutic purposes has been pursued for decades. As the clinical utility of anabolic-androgenic steroids has been found to be limited because of their lack of tissue selectivity and associated off-target effects, alternative drug entities have been designed and are commonly referred to as selective androgen receptor modulators (SARMs). While most of these SARMs are of nonsteroidal structure, the drug candidate MK-0773 comprises a 4-aza-steroidal nucleus. Besides the intended therapeutic use, SARMs have been found to be illicitly distributed and misused as doping agents in sport, necessitating frequently updated doping control analytical assays. As steroidal compounds reportedly undergo considerable metabolic transformations, the phase-I metabolism of MK-0773 was simulated using human liver microsomal (HLM) preparations and electrochemical conversion. Subsequently, major metabolic products were identified and characterized employing liquid chromatography-high-resolution/high- accuracy tandem mass spectrometry with electrospray (ESI) and atmospheric pressure chemical ionization (APCI) as well as nuclear magnetic resonance (NMR) spectroscopy. MK-0773 produced numerous phase-I metabolites under the chosen in vitro incubation reactions, mostly resulting from mono- and bisoxygenation of the steroid. HLM yielded at least 10 monooxygenated species, while electrochemistry-based experiments resulted predominantly in three monohydroxylated metabolites. Elemental composition data and product ion mass spectra were generated for these analytes, ESI/APCI measurements corroborated the formation of at least two N-oxygenated metabolites, and NMR data obtained from electrochemistry-derived products supported structures suggested for three monohydroxylated compounds. Hereby, the hydroxylation of the A-ring located N- bound methyl group was found to be of particular intensity. In the absence of controlled elimination studies, the produced information enables the implementation of new target analytes into routine doping controls and expands the focus of anti-doping efforts concerning this new anabolic agent.

Estimates of Octanol-Water Partitioning for Thousands of Dissolved Organic Species in Oil Sands Process-Affected Water.

In this study, the octanol-water distribution ratios (DOW, that is, apparent KOW at pH 8.4) of 2114 organic species in oil sands process-affected water were estimated by partitioning to polydimethylsiloxane (PDMS) coated stir bars and analysis by ultrahigh resolution orbitrap mass spectrometry in electrospray positive ((+)) and negative ((-)) ionization modes. At equilibrium, the majority of species in OSPW showed negligible partitioning to PDMS (i.e., DOW <1), however estimated DOW's for some species ranged up to 100,000. Most organic acids detected in ESI- had negligible partitioning, although some naphthenic acids (O2(-) species) had estimated DOW ranging up to 100. Polar neutral and basic compounds detected in ESI+ generally partitioned to PDMS to a greater extent than organic acids. Among these species, DOW was greatest among 3 groups: up to 1000 for mono-oxygenated species (O(+) species), up to 127,000 for NO(+) species, and up to 203,000 for SO(+) species. A positive relationship was observed between DOW and carbon number, and a negative relationship was observed with the number of double bonds (or rings). The results highlight that nonacidic compounds in OSPW are generally more hydrophobic than naphthenic acids and that some may be highly bioaccumulative and contribute to toxicity.

Oxidative dehydrogenation of propane with nitrous oxide over Fe–O–Al species occluded in ZSM-5: Reaction and deactivation mechanisms

Fe-ZSM-5 was prepared via solid-state exchange method using ferrocene as iron precursor and applied as a model catalyst to investigate the reaction and deactivation mechanisms of the oxidative dehydrogenation of propane (ODHP) with nitrous oxide. Characterization results reveal that after severe calcination highly isolated Fe–O–Al species are the only exposed iron sites detectable, which account for ca. 60% of the total iron species in Fe-ZSM-5. Results from temperature-programmed experiments and in situ DRIFT spectroscopy suggest that the chemisorption of nitrous oxide on Fe–O–Al species leads to the formation of stable mono-oxygen species, which can react with gaseous propane to produce propylene with high selectivity. The accumulation of organic species in the catalyst is observed during the reaction, and the major organic species are determined to be alkylbenzenes. The accumulation rate and the specific constitution of alkylbenzenes are found to depend on the relative partial pressures of propane and nitrous oxide: lower N2O/C3H8 ratios result in formation of aromatics with smaller kinetic diameter, which are accumulated at a lower rate. This leads to lower deactivation rates and longer catalyst lifetimes. Remarkably, a superior stable propane conversion rate of ca. 13mmolgcat−1h−1 and a propylene production rate of ca. 6mmolgcat−1h−1 can be kept for >40h with a N2O/C3H8 ratio of 1:2.

Multiple Pathways for the Oxygenation of a Ruthenium(II) Dithiocarbamate Complex: S-Oxygenation and S-Extrusion

The reactions of Ru(bpy)(2)(N,N-dimethyldithiocarbamate)(+), 1, with O-atom-transfer reagents such as hydrogen peroxide, m-chloroperoxybenzoic acid, and oxone have been studied and several resulting derivatives isolated and structurally characterized. Both S-oxygenation and S-extrusion may occur depending upon reagent and conditions. Excess peroxygenation leads to a stable dioxygenate, Ru(bpy)(2)(N,N-dimethylthiocarbamatesulfinate-S,S)(+), 3. Stoichiometric oxygenation leads to mixtures of products from which two forms of monooxygenated species Ru(bpy)(2)(N,N-dimethylperoxydithiocarbamate-S,S), 2a, and Ru(bpy)(2)(N,N-dimethylperoxydithiocarbamate-O,S), 2b, and an S-extruded product, Ru(bpy)(2)(N,N-dimethylmonothiocarbamate)(+), 4, have been isolated as PF(6)(-) salts. The S,S-bound monooxygenate is unstable over time toward either O-atom-transfer reactions via disproportionation or reaction with phosphines or S-extrusion yielding complex 4 in which the thiocarbamate is bonded solely through the remaining S atom. All the complexes have been characterized by (1)H NMR, UV-vis, and mass spectroscopies, and all but the highly reactive 2a structurally determined by X-ray crystallography.

Anaerobic and aerobic complexation of Co(II) by a polyamine ditopic ligand containing the phenolic moiety

The basicity behavior and coordination properties of the ligand 2,6-bis-{[bis-(2-aminoethyl)-amino]methyl}-phenol ( L) in aqueous solution toward Co(II), are reported and discussed together with those of the species formed with Ni(II) and Cu(II) ions. Moreover, binuclear cobalt complexes of L were investigated as possible binders for molecular dioxygen. The studies were carried out using potentiometric measurements (298.1 K, I=0.15 mol dm −3), UV–Vis absorption spectra, and 1H and 13C NMR spectra in aqueous solution. L behaves as a pentaprotic base in the range of the potentiometric measurements; the UV and NMR experiments revealed that in L, H L +, H 2 L 2+, and H 3 L 3+ species there is the simultaneous presence of positive and one negative charge on the ligand. L forms mono and binuclear complexes with Co(II) ion. The binuclear species occur with the complete deprotonation of L; the oxygen of the phenolate moiety bridges the two metal ions forcing them to stay close to each other, preorganizing the complexes to bind an additional molecule. This is the case of the binuclear cobalt species ([Co 2(H −1 L)(OH) j ] (3− j)+ ( j=0–2)), which cooperate to bind one molecule of dioxygen, giving rise to mono-oxygenated species. The stoichiometry of such species ([Co 2(H −1 L)(OH) j O 2] (3− j)+ ( j=0–2)), and other experimental data are in agreement with the formation of a μ-peroxocomplexes where the oxygen molecule bridges the two metal atoms. The experiments showed that the oxygenation reactions are reversible.

Use of chiral liquid chromatography–tandem mass spectrometry to investigate the metabolism of racemic cholecystokinin-B antagonists

In an attempt to establish the enantiomeric specificity of metabolism for a series of racemic cholecystokinin-B receptor antagonists, chiral LC–MS–MS conditions were established using a Pirkle DNBL chiral stationary phase operating in the reversed-phase mode. Rat liver microsomal incubations of the compounds were analysed using these conditions and it was demonstrated that resolution of oxygenated and demethylated metabolites could be achieved. A single model compound was investigated in detail by obtaining product-ion spectra on all mono-oxygenated species in an attempt to correlate these and identify enantiomeric pairs of metabolites. In this example a lack of differentiation in the product ion spectra did not allow correlation but the results suggest that such an approach may still be viable for the chiral metabolic analysis of racemic material.

Raman Spectroscopic and TPR Studies of Oxygen Species over BaO- and BaX2(X=F, Cl, Br)-Promoted Nd2O3Catalysts for the Oxidative Coupling of Methane

The 30 mol% BaO- and 30 mol% BaX2(X=F, Cl, Br)-promoted Nd2O3catalysts have been investigated for the oxidative coupling of methane (OCM). The addition of BaO or BaX2to Nd2O3could obviously enhance the catalytic performance. We observed leaching of halide during the OCM reaction. The stability of the halide ions follows the order: F−> Cl−> Br−. XRD and Raman results revealed that the addition of BaO or BaX2has significantly altered the surface and bulk natures of Nd2O3. The enlargement of Nd2O3lattice in the BaO- and BaX2-promoted Nd2O3catalysts was due to ionic exchange between Ba2+and Nd3+orX−and O2−ions. Raman results showed that there were dioxygen species such as O2−2, On−2, O−2, and Oδ−2on the surface when BaO or BaX2was added to Nd2O3. We suggest that the lattice defects generated due to ionic exchanges could promote the formation of dioxygen adspecies. TPR results implied that, besides the dioxygen species, there were mono-oxygen species existing in these catalysts. By pulsing CH4over the catalysts, we found that both dioxygen and mono-oxygen species could activate CH4at high temperatures and the existence of dioxygen species could improve the catalytic performance, especially in the enhancement of C2selectivity and C2H4/C2H6ratio.

Activation of O2 over SrF2- and BaF2-promoted SmOF catalysts for the oxidative dehydrogenation of ethane

Promotion of rhombohedral SmOF by SrF 2 or BaF 2 led to significant gain in ethane conversion but little change in ethene selectivity in the oxidative dehydrogenation of ethane. At 893 K, C 2 H 6 conversion and C 2 H 4 selectivity over SmOF were, respectively, 38.8 and 71.2%. With 10% SrF 2 /SmOF and 20% BaF 2 /SmOF catalysts, C 2 H 6 conversion became 69.7 and 68.4%, respectively, while C 2 H 4 selectivity was 67.7%. X-Ray diffraction (XRD) studies revealed a small amount of cubic SrF 2 but no crystal phase of BaF 2 in the promoted catalysts. The SrF 2 lattice contracted slightly and the SmOF lattices expanded slightly. We believe that such deformities resulted from ionic exchange/substitution occurring between/within the SrF 2 and SmOF phases with creation of active centres. The Raman and O 2 temperature programmed desorption (TPD) results, indicated that, above 973 K, dioxygen species on SmOF were converted completely to mono-oxygen species. With the promoted catalysts, such conversion was complete at around 573 K. Because Sm 3+ is paramagnetic and owing to the effect of spin–spin interaction, we could not obtain any EPR signals of O 2 - or O - over SmOF. Over the promoted catalysts, however, EPR signals corresponding to O 2 - and O - located in the proximity of non-paramagnetic Sr 2+ and Ba 2+ ions were observed. The conversion of O 2 - to O - was confirmed and monitored by EPR spectroscopy. We conclude that the deformities generated in the promoted catalysts have facilitated the conversion of dioxygen species to O - species at lower temperature, resulting in better catalytic performance.

The activation of O2 and the oxidative dehydrogenation of C2H6 over SmOF catalyst

The activation of O2 over SmOF was studied by in situ laser Raman spectrometry and temperature programmed desorption (TPD). When the hydrogen- and helium-treated (1 h for each gas at 973 K) SmOF sample was cooled to 303 K in oxygen, Raman bands which correspond to the existence of O22−, O2n− (2 >n > 1), O2− and O2δ-(1 >δ > 0) species were observed. From 303 to 973 K, there was no O2 desorption but the Raman bands observed at 303 K reduced in intensity and vanished completely at 973 K, even though the sample was under an atmosphere of oxygen. We suggest that as the sample temperature increased, dioxygen species were converted to mono-oxygen species such as O− which were undetectable by Raman spectrometry. O2 desorption occurred above 973 K, giving a TPD-peak at 1095 K. When C2 H6 was pulsed over the sample pretreated with oxygen and helium at 973 K, C2H4 selectivity was 91.8%. We conclude that the mono-oxygen species is responsible for the oxidative dehydrogenation of ethane to ethene.

Mechanism of the Acyl-Carbon Cleavage and Related Reactions Catalyzed by Multifunctional P-450s: Studies on Cytochrome P-45017.alpha.

It is now well-known that conventional cytochrome P-450s catalyze hydroxylation reactions using an iron mono-oxygen species, the structure of which, as inferred from chemical model studies, may be drrepresented by the following canonical forms: FeV==O<-->(.+)FeIV==O<-->FeIV--O(.). Certain multifunctional P-450s, notably those involved in steroid biosynthesis, catalyze, in addition to hydroxylation reactions, an acyl-carbon cleavage process in which the participation of an iron peroxide intermediate, FeIII--OOH, has been suggested. However the possibility still exists that the C--C bond cleavage may also occur using the FeV==O species. We have scrutinized the chemical consequences of involving either an FeV==O or an FeIII--OOH species for five different C--C bond cleavage reactions. With respect to the status as well as the origin of hydrogen and oxygen atoms, in four of the examples the mechanism involving the FeV==O species makes the same prediction as that using the iron peroxide intermediate, that is, the incorporation of an atom of oxygen from O2 into acyl part of the cleaved fragment. The fifth example, however, involving the formation, with pig testes microsomes, of 17 alpha-hydroxyandrogen (androst-5-ene-3 beta,17 alpha-diol) from pregnenolone, presents an interesting contrast--in this case different outcomes are predicted by the two mechanisms. These possibilities have been experimentally evaluated using substrates stereo- and regiospecifically labeled with heavy isotopes and incubated with pig testes microsomes under either 16O2 or 18O2.(ABSTRACT TRUNCATED AT 250 WORDS)

The redox thermodynamics for dioxygen species (O2, O2-., HOO., HOOH, and HOO-) and monooxygen species (O, O-., .OH, and -OH) in water and aprotic solvents.

Biological systems activate dioxygen (O2) by reduction via electron transfer and H-atom transfer to give intermediates that may be further activated by transition metals in proteins and metabolic co-factors. The reaction thermodynamics for these processes are influenced by the solution matrix and its acidity. Thus, the redox thermodynamics of O2 are directly dependent upon proton activity, O2 + 4H+ + 4e- → 2 H2O E°’ (1) which in turn depends upon the reaction matrix. Table 1 summarizes the pKa’ values for a series of Br0nsted acids in several aprotic solvents and water.1 In acetonitrile the activity values for pKa’ range from -8.8 for (H3O)ClO4 to 30.4 for H2O. This means that the formal potential (E°’) for reaction 1 in acetonitrile (MeCN) is +1.75 V vs. NHE in the presence of 1M(H3O)ClO4 and -0.56 V in the presence of IM (Bu4N)OH.

The mechanism of free base formation from DNA by bleomycin. A proposal based on site specific tritium release from Poly(dA.dU).

Poly(dA.dU), which is specifically tritiated at the 1'-, 2'- (ribo configuration), 3'-, or 4'-position of deoxyuridine, has been synthesized and the fate of the tritium has been determined upon degradation of the polymer by bleomycin, Fe(II), and O2. No tritium is labilized from the 1'-3H-labeled polymer as 3H2O; however, the resulting 3-(uridin-1'-yl)-2-propenal (uracil propenal) has the expected specific activity. The 2'-3H-labeled polymer affords 3H2O and no label in the uracil propenal. This result and the lack of solvent incorporation into the uracil propenal suggest that proton abstraction from C-2' to afford the trans-propenal is highly stereospecific. For the 3'-3H-labeled polymer, 3H2O is formed and the specific activity of the uracil propenal is identical to that of the deoxyuridine. This suggests that the labilization of the 3'-H is exclusively associated with free uracil formation. 3H2O is also formed from the 4'-3H-labeled polymer. These findings along with previous studies are consistent with the formation of uracil propenal and free uracil by the trapping of the initially formed 4'-radical species by O2 or by a monooxygen species, respectively.