HNO trapping and assisted decomposition of nitroxyl donors by ferric hemes

The role of nitric oxide (NO) as a signalling molecule in biological systems has been thoroughly studied in the last decades. More recently, there has been an increasing interest in the one-electron reduction product of NO, namely nitroxyl (HNO/NO⁻). Some studies suggest that nitroxyl can be produced by nitric oxide synthases under certain conditions, and that distinct pharmacological effects are observed for NO and nitroxyl donors. HNO is capable of react with heme proteins, thiols, molecular oxygen, NO and HNO itself. However, only recently the different reactivity patterns are being thoroughly understood. Heme model compounds offer the opportunity to study the reaction kinetics without the complexity arising from ligand interactions with the protein matrix. In this study we analyzed the reaction between the commonly used nitroxyl donors sodium trioxodinitrate and toluene sulfohydroxamic acid, with the ferric model compounds microperoxidase-11 (MP11) and the cationic metalloporphyrin [Fe^IIITEPyP]⁵⁺ (Tetrakis N-ethylpyridinium-2yl porphyne). Our results show that there are two alternative modes of reactivity for nitroxyl donors towards heme in aqueous solutions. The first one comprises the heme assisted decomposition of the donor, enhancing its decomposition rate more than 100-fold. In the second, the donor produces HNO which subsequently reacts with the porphyrin. The observed rate constants (of about 10⁵ M⁻¹ s⁻¹) are consistent with the estimated data for the HNO reaction with heme proteins, and may be controlled by the leaving water ligand. This rate constant probably represents an upper limit for the bimolecular rate constant of HNO towards these proteins.     

Hydrolysis of acyloxy nitroso compounds yields nitroxyl (HNO)

Nitroxyl (HNO/NO(-)), the reduced form of nitric oxide, has gained attention based on its separate chemistry and biology from nitric oxide. The inherent reactivity of HNO requires new and mechanistically unique donors for the detailed study of HNO chemistry and biology. Oxidation of cyclohexanone oxime with lead tetraacetate yields 1-nitrosocyclohexyl acetate, whereas oxidation of oximes in the presence of excess carboxylic acid gives various acyloxy nitroso compounds. These bright blue compounds exist as monomers as indicated by their infrared, proton, and carbon NMR spectra, and X-ray crystallographic analysis reveals the nitroso groups possess a "nitroxyl-like" bent configuration. Hydrolysis of these compounds produces nitrous oxide, the dimerization and dehydration product of HNO, and provides evidence for the intermediacy of HNO. Both thiols and oxidative metal complexes inhibit nitrous oxide formation. Hydrolysis of these compounds in the presence of ferric heme complexes forms ferrous nitrosyl complexes providing further evidence for the intermediacy of HNO. Kinetic analysis shows that the rate of hydrolysis depends on pH and the structure of the acyl group of the acyloxy nitroso compound. These compounds relax pre-constricted rat aortic rings similar to known HNO donors. Together, these results identify acyloxy nitroso compounds as a new class of HNO donors.     

Optimization of HNO production from N,O-bis-acylated hydroxylamine derivatives

A wide range of N,O-bis-acylated hydroxylamine derivatives with chloro or arenesulfonyl leaving groups, and a related set of N-hydroxy-N-acylsulfonamides, have been synthesized and evaluated for nitroxyl (HNO) production. Mechanistic studies have revealed that the observed aqueous chemistry is more complicated than originally anticipated, and have been used to develop a new series of efficient HNO precursors (4u-4x, 7c-7d) with tunable half-lives.     

Photoinduced Upregulation of Calcitonin Gene-Related Peptide in A549 Cells through HNO Release from a Hydrophilic Photocontrollable HNO Donor

Nitroxyl (HNO), a one-electron-reduced form of nitric oxide, has various biological activities, including a cardioprotective effect. Here, we first synthesized another, more hydrophilic photocontrollable HNO donor (3), which can release HNO in a spatially and temporally controlled manner, and then examined the properties of our series of compounds as practical HNO donors in a cellular system under photocontrol. We selected compound 2 as the preferred donor, and used it to show that calcitonin gene-related peptide (CGRP) can be upregulated in A549 cells via photocontrolled HNO release. This result demonstrates the suitability of this photocontrollable HNO donor for biological investigations.     

Stannyl ceramides as efficient acceptors for synthesising beta-galactosyl ceramides

beta-Galactosyl ceramides have been obtained in excellent yields and stereoselectivities by reacting disarmed glycosyl donors with stannyl ethers. The broad compatibility of stannyl ethers with various leaving group-promoter pairs is demonstrated.     

Discrimination of nitroxyl and nitric oxide by water-soluble Mn(III) porphyrins

The water-soluble manganese(III) meso-tetrakis (N-ethylpyridinium-2-yl) porphyrin (Mn(III)TEPyP) and manganese(III) meso-(tetrakis(4-sulfonato-phenyl)) porphyrinate (Mn(III)TPPS) are able to chemically distinguish between HNO and NO donors, reacting with the former in a fast, efficient, and selective manner with concomitant formation of the {MnNO}(7) complex (k(on(HNO)) approximately equal to 10(5) M(-1) s(-1)), while they are inert or react very slowly with NO donors. DFT calculations and kinetic data suggest that HNO trapping is operative at least in the case of Mn(III)TPPS, while catalytic decomposition of the HNO donors (sodium trioxodinitrate and toluene sulfohydroxamic acid) seems to be the main pathway for Mn(III)TEPyP. In the presence of oxygen, the product Mn(II)TEPyP(NO) oxidizes back to Mn(III)TEPyP, making it possible to process large ratios of nitroxyl donor with small amounts of porphyrin.     

Synthesis of β-O-glycosides using enol ether and imidate derived leaving groups. Emphasis on the use of nitriles as a solvent

Two new methods of β-glycoside synthesis using donors 2 and 3 that contain leaving groups derived from enol ether and imidates have been developed. Effect of nitriles as a solvent in directing mainly β-glycosidations has been compared with various methods reported in the literature. Effectiveness of leaving group at low temperatures and participation of nitriles in the formation of nitrilium—nitrile conjugate has been emphasized.     

Concise synthesis of 5-methoxy-6-hydroxy-2-methylchromone-7-O- and 5-hydroxy-2-methylchromone-7-O-rutinosides. Investigation of their cytotoxic activities against several human tumor cell lines

The synthesis of two novel 2-methylchromone-7-O-rutinosides is reported, and the in vitro biological activities of these compounds and their synthetic precursors have been investigated on the basis of their cytotoxicity against several human tumor cell lines. The synthesis features early stage assembly of the acidic labile glycosidic bond between sugar and 2-methylchromone aglycon under phase transfer catalyzed glycosidation conditions, whereas all the other standard glycosylation conditions specific to a wide array of rutinosyl donors bearing different anomeric leaving groups (e.g., SPh, OC(NH)CCl(3), Br, OH groups) failed to furnish any detectable products.     

Thermal studies on addition compounds of bis(ethylxathato)nickel(II)

Ni(xanthate)₂, a diamagnetic square planar complex forms 1:1 six-coordinated high-spin paramagnetic adducts with dinitrogen donors in different organic solvents. The thermal studies of these compounds show the loss of trapped solvent(ether) followed by the loss of the addendum leaving behind the parent xanthate complex. In the compounds with 1:3 ratio of Ni(xanthate): dinitrogen donors, the xan^? acts as an anion. The different steps of thermal decomposition in the compounds, Ni(phen)₃xan₂ and Ni(bipy)₃xan₂, can be explained on the basis of the conformational rigidity of the ligands. For the parent compound Ni(xan)₂, its 1:1 and 1:3 adducts as well as the thermal decomposition products (residues) have been analysed by chemical and physical methods. New intermediate complexes with the composition, Ni(phen)₂xan₂, Ni(bipy)S₂ and Ni(bipy)S have been obtained from the decomposition process, leading finally to NiO. The kinetic parameters were calculated using five different methods to check the applicability of these standard methods towards the elucidation of the decomposition mechanism.     

An investigation of the reactions of H3O+ and O2+ with NO, NO2, N2O and HNO2 in support of selected ion flow tube mass spectrometry

A selected ion flow tube (SIFT) experimental investigation has been carried out of the reactions of H3O+, NO+ and O2+ with NO, NO2, N2O and HNO2, in order to obtain the essential kinetic data for the analyses of these compounds in air using selected ion flow tube mass spectrometry (SIFT-MS). These investigations show that NO+ ions do not react at a significant rate with any of these NOx compounds and that H3O+ ions react only with HNO2 (product ions H2NO2+ (75%) and NO+ (25%)). O2+ ions react with NO (product ion NO+), NO2 (product ion NO2+) and HNO2 (product ions NO+ (75%), NO2+ (25%)), but not with N2O. We conclude that both NO and NO2 can be accurately quantified in air using only O2+ precursor ions and SIFT-MS when HNO2 is not present. However, when HNO2 is present it invariably co-exists with both NO and NO2 and then both H3O+ and O2+ precursor ions are needed to determine the partial pressures of NO, NO2 and HNO2 in the air mixture. We also conclude that currently N2O cannot be analysed in air using SIFT-MS.     

Rhamnosylation: diastereoselectivity of conformationally armed donors

The α/β-selectivity of super-armed rhamnosyl donors have been investigated in glycosylation reactions. The solvent was found to have a minor influence, whereas temperature was crucial for the diastereoselectivity. At very low temperature, a modest β-selectivity could be obtained, and increasing temperature gave excellent α-selectivity. The donors were highly reactive, and activation was observed at temperatures as low as -107 °C. Different promoter systems and leaving groups were investigated, and only activation with a heterogeneous catalyst increased the amount of the β-anomer significantly. By introducing an electron-withdrawing nonparticipating group, benzyl sulfonyl, on 2-O, an increase in β-product was observed.     

HNO and NO release from a primary amine-based diazeniumdiolate as a function of pH

The growing evidence that nitroxyl (HNO) has a rich pharmacological potential that differs from that of nitric oxide (NO) has intensified interest in HNO donors. Recently, the diazeniumdiolate (NONOate) based on isopropylamine (IPA/NO; Na[(CH(3))(2)CHNH(N(O)NO)]) was demonstrated to function under physiological conditions as an organic analogue to the commonly used HNO donor Angeli's salt (Na(2)N(2)O(3)). The decomposition mechanism of Angeli's salt is dependent on pH, with transition from an HNO to an NO donor occurring abruptly near pH 3. Here, pH is shown to also affect product formation from IPA/NO. Chemical analysis of HNO and NO production led to refinement of an earlier, quantum mechanically based prediction of the pH-dependent decomposition mechanisms of primary amine NONOates such as IPA/NO. Under basic conditions, the amine proton of IPA/NO is able to initiate decomposition to HNO by tautomerization to the nitroso nitrogen (N(2)). At lower pH, protonation activates a competing pathway to NO production. At pH 8, the donor properties of IPA/NO and Angeli's salt are demonstrated to be comparable, suggesting that at or above this pH, IPA/NO is primarily an HNO donor. Below pH 5, NO is the major product, while IPA/NO functions as a dual donor of HNO and NO at intermediate pH. This pH-dependent variability in product formation may prove useful in examination of the chemistry of NO and HNO. Furthermore, primary amine NONOates may serve as a tunable class of nitrogen oxide donor.     

Global ab initio potential energy surfaces for both the ground (X̃1A') and excited (Ã1A') electronic states of HNO and vibrational states of the Renner-Teller Ã1A'-X̃1A' system

The global potential energy surfaces for both the ground (X?(1)A(')) and excited (A?(1)A(')) electronic states of the HNO molecule have been constructed by three-dimensional cubic spline interpolation of more than 17,000 ab initio points, which have been calculated at the internal contracted multi-reference configuration interaction level with the Davidson correction using an augmented correlation-consistent polarized valence quadruple zeta basis set. The low-lying vibrational energy levels for the two electronic states of HNO have also been calculated on our potential energy surfaces including the diagonal Renner-Teller terms. The calculated results have shown a good agreement with the experimental vibrational frequencies of HNO and its isotopomers.     

Theoretical study of stratospheric relevant anions: nitrate-nitric acid complexes

The ion complexes NO3-(HNO3)n, n = 1-3, have been studied by means of ab initio calculations at the B3LYP/aug-cc-pVTZ level of theory. These systems are the most abundant anionic clusters below approximately 30 km altitude in the stratosphere and also in the upper troposphere. These complexes display short strong hydrogen bonds, which should be considered to explain their abundance in the atmosphere. Equilibrium geometries, harmonic frequencies, relative energies, and thermochemical data have been calculated for these anions for the first time. The calculations indicate small differences of energy in the variation of the two nitrate groups from planarity to an almost perpendicular form for n = 1. Planar geometries are found for n = 2 and 3 to give rise to a highly symmetric C(3h) NO3-(HNO3)3. In all the cases, binding energies close to those of covalent compounds are estimated. When experimental data are available, good correlations are found with our results.     

The effect of nitro substitution on the photochemistry of benzyl benozhydroxamate: Photoinduced release of benzohydroxamic acid

The redox congener of the important signaling agent nitric oxide (NO), nitroxyl or nitrosyl hydride (HNO) has also been demonstrated to induce distinct physiological effects. The aim of this study was to determine if benzohydroxamic acid, which was selected as a stable model compound of HNO donors, could be released by the o-nitrobenzyl photolabile protecting group (PPG) in a wavelength-dependent manner. It was expected that selective irradiation of the o-nitrobenzyl chromophore would favor the release of benzohydroxamic acid over undesired products associated with N-O bond cleavage. Quantum yields for the release of benzohydroxamic acid protected by the o-nitrobenzyl PPG increased at longer wavelengths, with a concomitant decrease in the yield of minor products. Through the use of triplet photosensitizers, triplet quenchers, computational methods, and the position of the nitro substituent, insights into the nature of the mechanism were suggested.     

Stability of pyrrolidone derivatives against γ-ray irradiation

To evaluate the stability of N-alkylated pyrrolidone derivatives(NRPs),which are supposed to be used as precipitants for U(VI) and Pu(IV,VI) species in HNO 3 media,under irradiation environment,some candidate NRPs were irradiated by γ-ray.Irradiation to HNO 3 solutions up to 6 mol dm 3(= M) containing 2 M N-n-butyl-2-pyrrolidone(NBP),one of NRPs with lower hydrophobicity,has revealed that the residual ratios of NBP in the samples of HNO 3 up to 3 M decreased identically and linearly.Approximately 20% of NBP was found to be degraded after the irradiation at 1 MGy.It was also found that the decrease in the precipitation ratio of UO 2 2+(P.R.,%) was gentle and that the P.R.values were relatively in accordance with the residual ratios of NBP.On the other hand,the degradation of the samples irradiated in 6 M HNO 3 was found more distinguished.It was proposed from the analyses of degraded compounds that the degradation of NBP in HNO 3 by γ-ray irradiation started from the cleavage of the pyrrolidone ring by the addition of oxygen atom originating from HNO 3,followed by the formation of chain compounds by the successive addition of oxygen,leading to the generation of oxalic acid and acetic acid.The stability of other NRPs in 3 M HNO 3 was evaluated to be nearly identical with that of NBP except lower P.R.values of the samples containing NRPs with higher hydrophobicity irradiated at more than 0.5 MGy.     

Characterization of diazeniumdiolate nitric oxide donors (NONOates) by electrospray ionization mass spectrometry

Diazeniumdiolates (also called NONOates) have been analyzed by electrospray ionization mass spectrometry (ESI-MS). The samples used are commercially available and included Diethylamine NONOate, DETA NONOate, Spermine NONOate, MAHMA NONOate, PROLI NONOate, Dipropylenetriamine NONOate, PAPA NONOate, and Sulpho NONOate. These compounds have been found to ionize upon ESI by protonation, deprotonation and sodiation. The MS(n) experiments provided strong evidence that such ions release NO, HNO, N(2)O, NO(2), N(2)O(2), N(3)O(3), N(4)O(3) and N(4)O(4) when collisionally activated. Thus, the facile donation of NO units is a property of such compounds. Negative-mode mass spectrometry has been particularly useful for the analysis of most of the NONOates studied here. The experiments have demonstrated the capabilities of mass spectrometry, along with CAD (MS/MS), to detect and characterize such compounds.     

Azanone (HNO): generation,stabilization and detection

HNO (nitroxyl, azanone), joined the ‘biologically relevant reactive nitrogen species’ family in the 2000s. Azanone is impossible to store due to its high reactivity and inherent low stability. Consequently, its chemistry and effects are studied using donor compounds, which release this molecule in solution and in the gas phase upon stimulation. Researchers have also tried to stabilize this elusive species and its conjugate base by coordination to metal centers using several ligands, like metalloporphyrins and pincer ligands. Given HNO''s high reactivity and short lifetime, several different strategies have been proposed for its detection in chemical and biological systems, such as colorimetric methods, EPR, HPLC, mass spectrometry, fluorescent probes, and electrochemical analysis. These approaches are described and critically compared. Finally, in the last ten years, several advances regarding the possibility of endogenous HNO generation were made; some of them are also revised in the present work.

HNO (nitroxyl, azanone), joined the ‘biologically relevant reactive nitrogen species’ family in the 2000s.     

10-甲基吖啶苯酚酯衍生物的合成、表征及化学发光特性

吖啶-9-羧酸苯酚酯是一类效率较高的化学发光试剂.其结构一般有两部分组成,吖啶环发光部分和9-羧酸苯酚酯离去基团.本文对离去基团进行修饰,分别在离去基团苯酚部分的2,5或2,6位引入取代基CF₃、NO₂、Br、CH₃,合成了4个新吖啶酯衍生物,并对它们的分子结构进行了表征.4个新化合物和模型化合物(无取代基)比较,均表现出较好的化学发光效率;发光动力学基本符合文献报道规律.而且化学发光法对其水解稳定性考察显示,取代基的电性和位阻是影响稳定性的两大因素.     

Raman spectra of complexes of HNO3 and NO3- with NO2 at surfaces and with N2O4 in solution

Raman spectra of HNO(3).NO(2) have been detected on liquid and solid surfaces in the presence of concentrated HNO(3) and NO(2) gas. The Raman spectrum of HNO(3) solutions containing N(2)O(4) has been partly reinterpreted in terms of contributions from HNO(3).N(2)O(4) and N(2)O(4).NO(3)(-) complexes.