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Chagas disease is a health problem that affects millions of persons, currently Nifurtimox (Nfx) and Benznidazole (Bz) are the unique drugs to treat it. However, these drugs produce adverse effects and high toxicity, which has motivated the search for new candidate drugs. Based on reports about the extensive biological activity of steroidal nitrate esters, in this study three nitrate esters steroids (1b, 2b and 4b) were synthetized and characterized from Dehydroepiandrosterone (DHEA, 1a), 19-hydroxy-DHEA (2a), and Androst-5-en-3β,17β-diol (4a), respectively. In addition, compounds 3a and 3b were obtained by introducing an α-ethynyl and a β-hydroxyl groups at position 17 of 2b and further nitration of the hydroxyl group. The trypanocidal activity of these steroids was evaluated in vitro against the epimastigote stage of two T. cruzi strains, Ninoa and TH, and their cytotoxicity over J774.2 macrophage cell line was assayed. Compounds 3a, 3b, and 4a shown higher trypanocidal activity than Bz and Nfx against epimastigotes of Ninoa strain, whereas DHEA (1a) and its nitrate derivative 1b showed higher activity than the reference drugs against the TH strain epimastigote. None of the compounds showed activity in the ex vivo assays against the blood trypomastigote of both strains. Interestingly, the selectivity index of Androst-5-en-3β,17β-diol 4a was almost twice the value of Nfx and 50 times more than Bz, against Ninoa and TH strains, respectively. Therefore, compound 4a could represent a valuable starting point toward the optimization of steroid derivatives as trypanocidal agents., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Nitrated-pyrazole-based energetic compounds have attracted wide publicity in the field of energetic materials (EMs) due to their high heat of formation, high density, tailored thermal stability, and detonation performance. Many nitrated-pyrazole-based energetic compounds have been developed to meet the increasing demands of high power, low sensitivity, and eco-friendly environment, and they have good applications in explosives, propellants, and pyrotechnics. Continuous and growing efforts have been committed to promote the rapid development of nitrated-pyrazole-based EMs in the last decade, especially through large amounts of Chinese research. Some of the ultimate aims of nitrated-pyrazole-based materials are to develop potential candidates of castable explosives, explore novel insensitive high energy materials, search for low cost synthesis strategies, high efficiency, and green environmental protection, and further widen the applications of EMs. This review article aims to present the recent processes in the synthesis and physical and explosive performances of the nitrated-pyrazole-based Ems, including monopyrazoles with nitro, bispyrazoles with nitro, nitropyrazolo[4,3- c ]pyrazoles, and their derivatives, and to comb the development trend of these compounds. This review intends to prompt fresh concepts for designing prominent high-performance nitropyrazole-based EMs.

In the quest for alternative products that would conquer natural enzyme drawbacks, enzyme-like nanomaterials with controllable morphology, high catalytic activity, excellent stability, and reusability have gained extensive attention in recent years. Herein, a simple and versatile strategy based on basic deep eutectic solvents was used to create layered copper hydroxide nitrate (Cu 2 (OH) 3 NO 3 ) with a well-structured nanosheet-like morphology. The present nanosheets exhibited extraordinary oxidase and peroxidase-like activity. More importantly, these nanosheets have shown the ability to operate at low and high temperatures with appreciable stability and multiple reusabilities. Based on inhibiting the oxidase-like activity of the prepared Cu 2 (OH) 3 NO 3 , we designed a colorimetric sensing technique with a high-efficiency detection of biothiols in serum samples. Because of the simplicity and low-cost fabrication approach, our findings would be beneficial to the artificial enzyme research community as another facile and green tactics to fabricate heterogeneous artificial enzymes. Graphical abstract.

aza-Michael adducts of tricarbonyl(tropone)iron are synthesized by two different methods. Primary aliphatic amines and cyclic secondary amines participate in a direct aza-Michael reaction with tricarbonyl(tropone)iron under solvent-free conditions. Less nucleophilic aniline derivatives and more hindered secondary amines add efficiently to the cationic tropone complex formed by protonation of tricarbonyl(tropone)iron. While the protocol utilizing the cationic complex is less efficient overall for accessing the aza-Michael adducts than the direct, solvent-free addition to the neutral complex, it allows the use of a broader range of amine nucleophiles. Following protection of the amine of the aza-Michael adduct as a tert-butyl carbamate, the diene is decomplexed from the iron tricarbonyl fragment upon treatment with cerium(IV) ammonium nitrate to provide derivatives of 6-aminocyclohepta-2,4-dien-1-one. These products can serve as precursors to diverse compounds containing a seven-membered carbocyclic ring. Because the demetallation requires protection of the amine as a carbamate, the aza-Michael adducts of secondary amines cannot be decomplexed using the protocol described here.

A group of nitrate derivatives of naturally occurring sauropunol A and B were designed and synthesized. Nitric oxide (NO) releasing capacity and vasodilatory capacity studies were performed to explore the structure-activity relationship of resulted nitrates. Biological evaluation of these compounds revealed that most of the synthesized mononitrate derivatives demonstrated superior releasing capacity than isosorbide mononitrate (ISMN), and 2MNS-6 even demonstrated stronger NO releasing capacity than isosorbide dinitrate (ISDN). Two dinitrates, DNS-1 and DNS-2 , showed higher NO releasing capacity than ISDN. Evaluation of inhibitory activities to the contractions in mesenteric artery rings revealed that 2MNS-8 and DNS-2 showed stronger vasorelaxation activities than ISDN. High level of NO and soluble guanylyl cyclase (sGC) may be essential for the potent vasodilatory effect of DNS-2 . The vasodilatory effects of DNS-2 may result from cellular signal transduction of NO-sGC-cGMP. DNS-2 was found to be the most potent sauropunol-derived nitrate vasodilatory agent for further pharmaceutical investigation against cardiovascular diseases.

A series of nitrate ester analogues of the acetaminophen derivative SCP-1 were prepared by triflic acid catalyzed O-acylation of SCP-1 with chloroalkanoyl chlorides followed by nitration with silver nitrate. The chloroesters and corresponding nitrate esters were obtained in high yields. Preliminary hepatotoxicity studies revealed nitrate esters 5b (MD-38) and 5c (MD-39) to be well tolerated by human hepatocytes and had little effect on the three cytochrome P450 enzymes tested (CYP3A4, CYP2E1 and CYP2D6). In addition, the nitrate ester 5c (MD-39) exhibited antipyretic activity similar to acetaminophen., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Fifty 1,3-dioxyxanthone nitrates (4a ∼ i-n, n = 1-6) were designed and synthesized based on molecular similarity strategy. Incorporation of nitrate into 1,3-dioxyxanthones with electron-donating groups at 6-8 position brought about synergistic anticancer effect. Among them, compound 4g-4 was confirmed the most active agent against HepG-2 cells growth with an IC 50 of 0.33 ± 0.06 μM. It dose-dependently increased intramolecular NO levels. This activity was attenuated by either NO scavenger PTIO or mitochondrial aldehyde dehydrogenase (mtADH) inhibitor PCDA. Apoptosis analysis indicated different contributions of early/late apoptosis and necrosis to cell death for different dose of 4g-4. 4g-4 arrested more cells on S phase. Results from Western Blot implied that 4g-4 regulated p53/MDM2 to promote cancer cell apoptosis. All the evidences support that 4g-4 is a promising anti-cancer agent., (Copyright © 2018 Elsevier Masson SAS. All rights reserved.)

The free radical nitric oxide (NO) is considered one of the most versatile endogenous molecules and is a crucial signalling molecule in numerous biochemistry pathways of the human body. NO is directly related to pathological processes and plays an important role in many different and interrelated physiological processes. In some cases, a depletion of NO or an attenuation of its effector system could exist as in hypertension, angina and impotence; in others, an overproduction of NO may be a major cause of damage, as in circulatory shock, sepsis, neurodegenerative disorders and inflammatory responses. By using certain functional groups present in molecules that already have potential therapeutic value, hybrid compounds, by means of inclusion of NO-donors (e.g., ester nitrates and nitrites, S-nitrosothiols, metal complexes, furoxans, oxadiazoles, diazeniumdiolates and NO nanoparticles), can be developed that have a NO release benefit along with maintaining the activity of the native drug. The objective of the design of NO-donor hybrid compounds is to achieve a balance between the release of therapeutic amounts of NO, especially in the site of action, and maintaining the native drug activity. This review explores some of the most promising recent advances in NO-donor drug development and addresses the challenges associated with NO as a therapeutic agent., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)

Thionitrates (R-SNO₂) have been proposed as key intermediates in the biotransformation of organic nitrates that have been used for the clinical treatment of angina pectoris for over 100 years. It has been proposed and widely accepted that a thiol would react with an organic nitrate to afford a thionitrate intermediate. However, there has been no example of an experimental demonstration of this elementary chemical process in organic systems. Herein, we report that aryl- and primary-alkyl-substituted thionitrates were successfully synthesized by the reaction of the corresponding lithium thiolates with organic nitrates by taking advantage of cavity-shaped substituents. The structure of a primary-alkyl-substituted thionitrate was unambiguously established by X-ray crystallographic analysis.

We recently reported the synthesis of NOSH-aspirin, a novel hybrid that releases both nitric oxide (NO) and hydrogen sulfide (H2S). In NOSH-aspirin, the two moieties that release NO and H2S are covalently linked at the 1, 2 positions of acetyl salicylic acid, i.e. ortho-NOSH-aspirin (o-NOSH-aspirin). In the present study, we compared the effects of the positional isomers of NOSH-ASA (o-NOSH-aspirin, m-NOSH-aspirin and p-NOSH-aspirin) to that of aspirin on growth of HT-29 and HCT 15 colon cancer cells, belonging to the same histological subtype, but with different expression of cyclooxygenase (COX) enzymes; HT-29 express both COX-1 and COX-2, whereas HCT 15 is COX-null. We also analyzed the effect of these compounds on proliferation and apoptosis in HT-29 cells. Since the parent compound aspirin, inhibits both COX-1 and COX-2, we also evaluated the effects of these compounds on COX-1 and COX-2 enzyme activities and also performed modeling of the interactions between the positional isomers of NOSH-aspirin and COX-1 and COX-2 enzymes. We observed that the three positional isomers of NOSH aspirin inhibited the growth of both colon cancer cell lines with IC50s in the nano-molar range. In particular in HT-29 cells the IC50s for growth inhibition were: o-NOSH-ASA, 0.04±0.011 µM; m-NOSH-ASA, 0.24±0.11 µM; p-NOSH-ASA, 0.46±0.17 µM; and in HCT 15 cells the IC50s for o-NOSH-ASA, m-NOSH-ASA, and p-NOSH-ASA were 0.062 ±0.006 µM, 0.092±0.004 µM, and 0.37±0.04 µM, respectively. The IC50 for aspirin in both cell lines was >5mM at 24h. The reduction of cell growth appeared to be mediated through inhibition of proliferation, and induction of apoptosis. All 3 positional isomers of NOSH-aspirin preferentially inhibited COX-1 over COX-2. These results suggest that the three positional isomers of NOSH-aspirin have the same biological actions, but that o-NOSH-ASA displayed the strongest anti-neoplastic potential., (Copyright © 2015 The Authors. Published by Elsevier B.V. All rights reserved.)

We recently reported the synthesis of NOSH-aspirin, a novel hybrid compound capable of releasing both nitric oxide (NO) and hydrogen sulfide (H2S). In NOSH-aspirin, the two moieties that release NO and H2S are covalently linked at the 1, 2 positions of acetyl salicylic acid, i.e., ortho-NOSH-aspirin. Here we report on the synthesis of meta- and para-NOSH-aspirins. We also made a head-to-head evaluation of the effects of these three positional isomers of NOSH-aspirin on colon cancer cell kinetics and induction of reactive oxygen species, which in recent years has emerged as a key event in causing cancer cell regression. Electron donating/withdrawing groups incorporated about the benzoate moiety significantly affected the potency of these compounds with respect to colon cancer cell growth inhibition., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

A regioselective green synthesis of nitroacetaminophen derivatives was carried out by electrochemical oxidation of acetaminophen, N-(2-hydroxyphenyl)acetamide, and 1-(4-(4-hydroxyphenyl)piperazin-1-yl)ethanone in the presence of nitrite ion as a nucleophile. The present work has led to the development of a reagentless green and facile electrochemical method for the synthesis of some nitroacetaminophen derivatives.

Herein we disclose the synthesis of 2-fluoro-2-deoxyisosorbide 5-mononitrate (2F-IS-5MN), a fluorinated analogue of the commonly prescribed vasodilator isosorbide 5-mononitrate (IS-5MN). X-ray structural data for IS-5MN and its C2-epimeric congener IM-5MN are presented together with structural data for 2F-IS-5MN. Radioisotope labeling of 2F-IS-5MN has, for the first time, allowed observation of the in vivo biodistribution of this organic nitrate by means of dynamic positron emission tomography (PET) in wild-type mice., (© 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Solid complexes of lanthanide nitrates with an novel multipodal ligand, 1,2,4,5-tetramethyl-3,6-bis{N,N-bis[((2'-furfurylaminoformyl)phenoxyl)ethyl]-aminomethyl}-benzene (L) have been synthesized and characterized by elemental analysis, infrared spectra and molar conductivity measurements. At the same time, the luminescent properties of the Sm(III), Eu(III), Tb(III) and Dy(III) nitrate complexes in solid state were investigated. Under the excitation of UV light, these complexes exhibited characteristic emission of central metal ions. The lowest triplet state energy level of the ligand indicates that the triplet state energy level (T1) of the ligand matches better the resonance level of Tb(III) than other lanthanide ions., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Transparent crystal of glycine barium nitrate (GBN) has been grown from aqueous solution by slow evaporation technique at room temperature. Powder XRD study reveals the crystalline nature of the grown sample. Single crystal XRD study shows that the GBN belongs to orthorhombic crystal system. FTIR spectral study confirms the presence of the functional groups in the grown crystal. The presence of wide transparency window in the UV-visible region makes GBN crystal suitable for opto-electronic device applications. The grown sample has SHG efficiency is 0.8 times that of standard KDP crystal. Dielectric studies reveal that both dielectric constant and dielectric loss decreases with increase in frequency. Photoconductivity study confirms the negative photoconducting nature of the crystal., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Criegee intermediates are formed in the ozonolysis of alkenes and play an important role in indoor chemistry, notably as a source of OH radicals. Recent studies have shown that these Criegee intermediates react very quickly with NO2 , SO2 , and carbonyls, and in this study, steady-state calculations are used to inspect the potential impact of these data on indoor chemistry. It is shown that these reactions could accelerate NO3 formation and SO2 removal in the indoor environment significantly. In addition, reaction between Criegee intermediates and halogenated carbonyls could provide a significant loss process indoors, where currently one does not exist., (© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

The gas-phase reaction of nitric acid with the amidogen radical under atmospheric conditions has been investigated using quantum mechanical (QCISD and CCSD(T)) and DFT (B3LYP, BH&HLYP, M05, M05-2X, and M06-2X) calculations with the 6-311+G(2df,2p), aug-cc-pVTZ, aug-cc-pVQZ and extrapolation to the CBS basis sets. The reaction begins with the barrierless formation of a hydrogen-bonded complex, which can undergo two different reaction pathways, in addition to the decomposition back to the reactants. The lowest energy barrier pathway involves a proton-coupled electron-transfer mechanism, whereas the highest energy barrier pathway takes place through a hydrogen atom transfer mechanism. The performance of the different DFT functionals in predicting both the geometries and relative energies of the stationary points investigated has been analyzed.

In the ocean, the chemical forms of nitrogen that are readily available for biological use (known collectively as 'fixed' nitrogen) fuel the global phytoplankton productivity that exports carbon to the deep ocean. Accordingly, variation in the oceanic fixed nitrogen reservoir has been proposed as a cause of glacial-interglacial changes in atmospheric carbon dioxide concentration. Marine nitrogen fixation, which produces most of the ocean's fixed nitrogen, is thought to be affected by multiple factors, including ocean temperature and the availability of iron and phosphorus. Here we reconstruct changes in North Atlantic nitrogen fixation over the past 160,000 years from the shell-bound nitrogen isotope ratio ((15)N/(14)N) of planktonic foraminifera in Caribbean Sea sediments. The observed changes cannot be explained by reconstructed changes in temperature, the supply of (iron-bearing) dust or water column denitrification. We identify a strong, roughly 23,000-year cycle in nitrogen fixation and suggest that it is a response to orbitally driven changes in equatorial Atlantic upwelling, which imports 'excess' phosphorus (phosphorus in stoichiometric excess of fixed nitrogen) into the tropical North Atlantic surface. In addition, we find that nitrogen fixation was reduced during glacial stages 6 and 4, when North Atlantic Deep Water had shoaled to become glacial North Atlantic intermediate water, which isolated the Atlantic thermocline from excess phosphorus-rich mid-depth waters that today enter from the Southern Ocean. Although modern studies have yielded diverse views of the controls on nitrogen fixation, our palaeobiogeochemical data suggest that excess phosphorus is the master variable in the North Atlantic Ocean and indicate that the variations in its supply over the most recent glacial cycle were dominated by the response of regional ocean circulation to the orbital cycles.

Aldose reductase (AR) plays an important role in the design of drugs that prevent and treat diabetic complications. Aldose reductase inhibitors (ARIs) have received significant attentions as potent therapeutic drugs. Based on combination principles, three series of luteolin derivatives were synthesised and evaluated for their AR inhibitory activity and nitric oxide (NO)-releasing capacity in vitro. Eighteen compounds were found to be potent ARIs with IC50 values ranging from (0.099±0.008) μM to (2.833±0.102) μM. O(7)-Nitrooxyethyl-O(3'),O(4')-ethylidene luteolin (La1) showed the most potent AR inhibitory activity [IC50=(0.099±0.008) μM]. All organic nitrate derivatives released low concentrations of NO in the presence of l-cysteine. Structure-activity relationship studies suggested that introduction of an NO donor, protection of the catechol structure, and the ether chain of a 2-carbon spacer as a coupling chain on the luteolin scaffold all help increase the AR inhibitory activity of the resulting compound. This class of NO-donor luteolin derivatives as efficient ARIs offer a new concept for the development and design of new drug for preventive and therapeutic drugs for diabetic complications., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Although recent evidence suggests that the heterogeneous reaction of NO2 on the surface of mineral aerosol plays an important role in the atmospheric chemistry, a fundamental understanding of how temperature influences the rate and extent of nitrate formation processes remains unclear. This work presents the first laboratory study of the effect of temperature on heterogeneous reaction of NO2 on the surface of γ-Al2O3 in the temperature range of 250-318 K at ambient pressure. From the analysis of IR spectra, nitrite was found to be an intermediate product at temperatures between 250 and 318 K. It is proved by our experiments that nitrite would convert to the bidentate nitrate as the reaction proceeded. In addition, it is interesting to find that the rate of conversion increased with decreasing temperature. Along with nitrite decrease, the initial rate of nitrate formation increased while the rate of nitrate formation in the steady region decreased with decreasing temperature. The uptake coefficients at seasonal temperatures were determined for the first time and were found to be sensitive to temperature. Finally, atmospheric implications of the role of temperature on the heterogeneous reaction of NO2 with mineral aerosol are discussed.

To search for potent anti-Alzheimer's disease (AD) agents with multifunctional effects, 12 NO-donating tacrine-flurbiprofen hybrid compounds (2a-l) were synthesized and biologically evaluated. It was found that all the new target compounds showed selective butyrylcholinesterase (BuChE) inhibitory activity in vitro comparable or higher than tacrine and the tacrine-flurbiprofen hybrid compounds 1a-c, and released moderate amount of NO in vitro. The kinetic study suggests that one of the most active and highest BuChE selective compounds 2d may not only compete with the substrate for the same catalytic active site (CAS) but also interact with a second binding site. Furthermore, 2d and 2l exhibited significant vascular relaxation effect, which is beneficial for the treatment of AD. All the results suggest that 2d and 2l might be promising lead compounds for further research., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Nitrated fatty acids are the product of nitrogen dioxide reaction with unsaturated fatty acids. The discovery of peroxynitrite and peroxidase-induced nitration of biomolecules led to the initial reports of endogenous nitrated fatty acids. These species increase during ischemia/reperfusion, but concentrations are often at or near the limits of detection. Here, we describe multiple methods for nitrated fatty acid synthesis and sample extraction from complex biological matrices and a rigorous method of qualitative and quantitative detection of nitrated fatty acids by liquid chromatography-mass spectrometry. In addition, optimized instrument conditions and caveats regarding data interpretation are discussed., (Copyright © 2012 Elsevier Inc. All rights reserved.)

ZJM-289 is a potent racemic agent which inhibits both platelet aggregation and thrombosis superior to a known anti-ischemic stroke drug 3-n-butylphthalide (NBP). Herein, the enantiomers of ZJM-289, (S)-ZJM-289 and (R)-ZJM-289, were synthesized and evaluated for their biological activities. It was observed that the two enantiomers appeared to be almost as effective as ZJM-289 in inhibiting platelet aggregation in vitro and thrombus formation in vivo. Moreover, like ZJM-289, its enantiomers could regulate the ratio of thromboxane B(2) (TXB(2)) and 6-keto-prostaglandin F(1α), and enhanced levels of nitric oxide (NO), cAMP and cGMP, suggesting that the anti-platelet and antithrombotic activities of the enantiomers and ZJM-289 are associated with both the arachidonic acid cascade and cGMP-NO signal pathway. Furthermore, it was found that oral administration of the enantiomers and ZJM-289 for three days significantly reduced the infarct size, brain water content and neurological deficit in rats after cerebral ischemia reperfusion. Importantly, the two enantiomers equally improved blood flow in the ischemic stroke model and modulated endothelial function through releasing moderate levels of NO, which might, at least partially, contribute to their neuroprotection. Collectively, the present study demonstrates that the two enantiomers are as potent as ZJM-289 in inhibition of platelet aggregation and thrombosis and in neuroprotection, and (S)-ZJM-289 shows somewhat better effects than (R)-ZJM-289 and ZJM-289 in a few cases. These findings may provide new insights into the development of therapeutic agents like ZJM-289 for the intervention of thrombosis-related ischemic stroke.

The reduced availability of nitric oxide (NO) is associated with cardiovascular diseases. Therefore, NO donors such as organic nitrates are useful for the treatment of these disorders. The 2-nitrate-1,3-dibuthoxypropan (NDBP) is an organic nitrate synthesized from glycerin, which the pharmacological effects have not been investigated. In this study we evaluated the vasorelaxant effect induced by NDBP in superior mesenteric artery from rats. In phenylephrine pre-contracted artery rings, NDBP (10(-8)-10(-4)M) elicited concentration-dependent and endothelium-independent relaxation, which were attenuated by hydroxocobalamin-HDX (30 μM), a NO extracellular scavenger, and 1-H-[1,2,4] oxadiazolo [4,3-a] quinoxalin-1-one-ODQ (10 μM), an inhibitor of soluble guanylyl cyclase (sGC). In addition, the NDBP-induced relaxation was reduced by non-selective K(+) channels blocker KCl (20 mM) or selective K(+) channels blockers such as tetraethylammonium-TEA (B(KCa), 1 mM), charybdotoxin-ChTX (B(KCa), 100 nM), glibenclamide (K(ATP), 1μM) and 4-aminopyridine-4-AP (K(V), 1mM). In preparations with ODQ (10 μM) plus TEA (1 mM), the response was virtually abolished. In rat smooth muscle cells culture, NDBP (10(-6)-10(-4)M) caused concentration-dependent increases in NO levels. These findings suggest that NDBP causes vasorelaxation through NO generation and activation of the sCG/cGMP/PKG pathway., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Hydrolysis of Bi(NO(3))(3) in aqueous solution gave crystals of the novel compounds [Bi(6)O(4)(OH)(4)(NO(3))(5)(H(2)O)](NO(3)) (1) and [Bi(6)O(4)(OH)(4)(NO(3))(6)(H(2)O)(2)]·H(2)O (2) among the series of hexanuclear bismuth oxido nitrates. Compounds 1 and 2 both crystallize in the monoclinic space group P2(1)/n but show significant differences in their lattice parameters: 1, a = 9.2516(6) Å, b = 13.4298(9) Å, c = 17.8471(14) Å, β = 94.531(6)°, V = 2210.5(3) Å(3); 2, a = 9.0149(3) Å, b = 16.9298(4) Å, c = 15.6864(4) Å, β = 90.129(3)°, V = 2394.06(12) Å(3). Variation of the conditions for partial hydrolysis of Bi(NO(3))(3) gave bismuth oxido nitrates of even higher nuclearity, [{Bi(38)O(45)(NO(3))(24)(DMSO)(26)}·4DMSO][{Bi(38)O(45)(NO(3))(24)(DMSO)(24)}·4DMSO] (3) and [{Bi(38)O(45)(NO(3))(24)(DMSO)(26)}·2DMSO][{Bi(38)O(45)(NO(3))(24)(DMSO)(24)}·0.5DMSO] (5), upon crystallization from DMSO. Bismuth oxido clusters 3 and 5 crystallize in the triclinic space group P1 both with two crystallographically independent molecules in the asymmetric unit. The following lattice parameters are observed: 3, a = 20.3804(10) Å, b = 20.3871(9) Å, c = 34.9715(15) Å, α = 76.657(4)°, β = 73.479(4)°, γ = 60.228(5)°, V = 12021.7(9) Å(3); 5, a = 20.0329(4) Å, b = 20.0601(4) Å, c = 34.3532(6) Å, α = 90.196(1)°, β = 91.344(2)°, γ = 119.370(2)°, V = 12025.8(4) Å(3). Differences in the number of DMSO molecules (coordinated and noncoordinated) and ligand (nitrate, DMSO) coordination modes are observed.

The branching ratio β = k(1b)/k(1a) for the formation of methyl nitrate, CH(3)ONO(2), in the gas-phase CH(3)O(2) + NO reaction, CH(3)O(2) + NO → CH(3)O + NO(2) (1a), CH(3)O(2) + NO → CH(3)ONO(2) (1b), has been determined over the pressure and temperature ranges 50-500 Torr and 223-300 K, respectively, using a turbulent flow reactor coupled with a chemical ionization mass spectrometer. At 298 K, the CH(3)ONO(2) yield has been found to increase linearly with pressure from 0.33 ± 0.16% at 50 Torr to 0.80 ± 0.54% at 500 Torr (errors are 2σ). Decrease of temperature from 300 to 220 K leads to an increase of β by a factor of about 3 in the 100-200 Torr range. These data correspond to a value of β ≈ 1.0 ± 0.7% over the pressure and temperature ranges of the whole troposphere. Atmospheric concentrations of CH(3)ONO(2) roughly estimated using results of this work are in reasonable agreement with those observed in polluted environments and significantly higher compared with measurements in upper troposphere and lower stratosphere.

An efficient and one pot synthetic method of ipso-nitration of arylboronic acids has been developed. The high efficiency, general applicability, and broader substrate scope including heterocycles and functional groups make this method advantageous. Due to its simplicity, we expect to find application of this method in synthesis.

Pharmacological compounds that release nitric oxide (NO) have been recognized as the potential therapeutic agents for acute stroke. (S)-ZJM-289 is a novel NO-releasing derivative of 3-n-butylphthalide (NBP) with enhanced anti-platelet and anti-thrombotic actions. The present study was performed to investigate the neuroprotective effects and related mechanisms of (S)-ZJM-289 on ischemic neuronal injury in vitro and in vivo. Primary cortical neuronal cultures were exposured to oxygen-glucose deprivation followed by recovery (OGD/R), a model of ischemia-like injury, and treated with (S)-ZJM-289 before OGD. In vitro results showed that (S)-ZJM-289 attenuated OGD/R-induced neuronal injury, which was associated with the maintenance of mitochondrial integrity and function by alleviating intracellular calcium overload and reactive oxygen species (ROS) accumulation, preventing mitochondrial membrane depolarization and preserving respiratory chain complexes activities. Moreover, (S)-ZJM-289 treatment suppressed mitochondrial release of cytochrome c (cyt c) and nuclear translocation of apoptosis-inducing factor (AIF), thereby blocking mitochondria-mediated cell death, which may be partially mediated by up-regulation of Hsp70. The neuroprotection by (S)-ZJM-289 was also studied using a model of middle cerebral artery occlusion (MCAO). Oral administration of (S)-ZJM-289 at the onset of reperfusion for 3d significantly reduced the brain infarct size, improved neurological deficit and prevented neuronal loss and apoptosis. In current study, (S)-ZJM-289 appears to be more potent in ischemic neuroprotection than NBP, in particular at the lower doses, which may be due to the synergistic action of NBP and NO. These findings point to that (S)-ZJM-289 could be an attractive alternative to NBP in preventing the process of ischemia/reperfusion (I/R) injury., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Most ischemic stroke results from brain blood vessel blockage by platelet-mediated thrombus, and anti-platelet therapy has been demonstrated clinical benefits in the treatment of this disease. In the present work, novel nitric oxide (NO)-releasing derivatives of an anti-ischemic stroke drug 3-n-butylphthalide (NBP) were synthesized. Compounds 7a and 7c exhibited more potent anti-platelet activity than NBP and aspirin, and released a moderate amount of NO, which is beneficial in improving cardiovascular and cerebral circulation. These findings provide an alternative approach to the development of drugs more potent than NBP for the intervention of ischemic stroke., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

We have designed cancer antiproliferative compounds, starting from aniline or phenol derivative, which comprise one or two nitrooxymethylphenyl groups as do the hybrid drugs NCX4040 and NCX530. Compound 2a with p-nitrooxymethylbenzoyl-oxy and -amino groups as well as 8a with a p-nitrooxymethylbenzoylamino group showed more promising effects than NCX4040 against human colon and breast cancer cells. Since 2a and 8a, but not NCX4040, arrested human colon carcinoma HCT116 cells in the M phase, the former two compounds may inhibit cell growth differently from NCX4040. Merged images of immunofluorescence-stained α-tubulin and Hoechst-stained nuclei in human fibrosarcoma HT1080 cells showed that 2a and 8a disrupted microtubule formation just as did vincristine, the tubulin polymerization inhibitor. In experiments in vivo, the intraperitoneal administration of 8a at 80 mg/kg/day reduced the growth of HCT116 xenografts in nude mice to T/C 55%., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Using Cd(NO(3))(2)·4H(2)O as a precursor and ethanol/water as the solvent, we synthesized Cd(5)(OH)(8)(NO(3))(2)(H(2)O)(2) nanowires and nanobelts through a simple solvothermal method. Unlike the conventional oil-water surfactant approach, the adopted method is biologically safe, simple and environmentally benign. The morphology and size of the obtained materials were studied by FESEM. The results revealed that it is possible to assemble nanowires into microblocks by changing the ethanol/water ratio. Furthermore, the results of XRD investigation suggested that the change of ethanol/water ratio can have an influence on the crystalloid phases of Cd(5)(OH)(8)(NO(3))(2)(H(2)O)(2). Through calcination of the as-synthesized compounds in air, nanoporous CdO can be generated. We found that the as-obtained CdO materials are photocatalytically active in the degradation of methylene blue. It is envisaged that this environmentally benign method is also suitable for the synthesis of nanostructures of other oxides such as MgO and CuO.

To find novel antihepatitis drugs, a series of nitrate-oleanolic acid (OA) hybrids (10a, 10b, 11a-11e and 12a-12c) were designed and synthesized on the basis of previous studies using OA as lead compound, which is widely found in natural plants and liver-specific metabolism. In the present study, ten novel NO-releasing derivatives of OA were synthesized by connecting nitrate to the OA-3-OH through varying lengths of linkers containing antioxidants which were designed to increase the ability of these target compounds to scavenge free radicals. The structures of these objective compounds were determined by IR, MS, 1H NMR and elemental analysis. Their protective effects on anti-Fas mediated HepG2 cell apoptosis were in vitro evaluated by LDH assay. Compound 12a is the most potent inhibitor. Its effect on anti-Fas mediated HepG2 cell apoptosis and amount of NO-releasing in vitro are similar to those of positive control NCX-1000.

Six derivatives of 1-(2-(benzoyl-(substituted)-2-phenyl-1H-indole-5-carbony) hydrazinyloxy) vinyl nitrate were synthesized and tested in vivo for anti-inflammatory, analgesic, and ulcerogenic properties. Synthesized compounds shown significant anti-inflammatory activity comparable to that of Diclofenac sodium in the carrageenan-induced rat paw edema test and all of the compounds were found to be equipotent to Diclofenac sodium in the acetic acid induced writhing analgesic model. Out of six derivatives two derivatives found to produce no ulceration in stomach specimen of rats; nitric oxide seems to contribute to their excellent safety profile which supports several endogenous GIT defense mechanisms, including increase in mucus, bicarbonate secretions, increase in mucosal blood flow, and inhibition of the activation of pro-inflammatory cells by which NO-Indomethacin protects GI mucosa.

Aspirin prodrugs and related nitric oxide releasing compounds hold significant therapeutic promise, but they are hard to design because aspirin esterification renders its acetate group very susceptible to plasma esterase mediated hydrolysis. Isosorbide-2-aspirinate-5-salicylate is a true aspirin prodrug in human blood because it can be effectively hydrolyzed to aspirin upon interaction with plasma BuChE. We show that the identity of the remote 5-ester dictates whether aspirin is among the products of plasma-mediated hydrolysis. By observing the requirements for aspirin release from an initial panel of isosorbide-based esters, we were able to introduce nitroxymethyl groups at the 5-position while maintaining ability to release aspirin. Several of these compounds are potent inhibitors of platelet aggregation. The design of these compounds will allow better exploration of cross-talk between COX inhibition and nitric oxide release and potentially lead to the development of selective COX-1 acetylating drugs without gastric toxicity.

Using a flow tube reactor coupled to a chemical ionization mass spectrometer, the Cl-initiated oxidation of solid and supercooled liquid brassidic acid (BA, trans-13-docosenoic acid) particles was investigated in the presence of NO and NO2. For the first time, organic nitrate formation from the heterogeneous oxidation of model organic aerosols in the presence of NO was observed, but none was formed by the addition of up to 600 ppb of NO2. Also, no nitrate formation was observed in liquid particles, but the nitrate yields in the solid particles were measured to be as large as 6% with a negative temperature dependence over the range 259-293 K. The corresponding effective activation energy of -7.5 (+/-4.4) kJ mol(-1) suggests that the mechanism of particulate organic nitrate formation is analogous to the termolecular gas-phase reaction of . The yields are smaller than those from analogous gas-phase reactions, but this may result from photodissociation of the nitrate by the UV (355 nm) laser for which there is indirect evidence. Additionally, enhanced rates of the RO2+RO2 reactions in the condensed phase could lead to smaller nitrate yields. The results suggest that slower diffusion of the RO2 radicals in the solid particles compared to the liquid particles makes the RO2+NO reaction competitive with the RO2+RO2 reactions and results in nitrate formation near the surface of the particle. The organic nitrates formed in these experiments are observed intact after the reacted particles have been vaporized at temperatures up to 380 degrees C suggesting that they are thermally stable in the troposphere and may enable long-range transport of NOx if they photodissociate on the timescale of days. The findings from these experiments are not specific to unsaturated carboxylic acids but should apply to nearly all particulate hydrocarbons, and they indicate that the particle phase could be important in determining how organic aerosols evolve chemically through radical-initiated oxidation in polluted atmospheres.

A series of (nitrooxyacyloxy)methyl esters of aspirin were synthesized and evaluated as new NO-donor aspirins. Different amounts of aspirin were released in serum from these products according to the nature of nitrooxyacyloxy moiety present. In the aromatic series, there is a rather good linear correlation between the amount of aspirin released and the potencies of the products in inhibiting platelet aggregation induced by collagen. Both the native compounds and the related nitrooxy-substituted acid metabolites were able to relax rat aorta strips precontracted with phenylephrine, in keeping with a NO-induced activation of the sGC as a mechanism that underlies the vasodilator effect. The products here described are new improved examples of NO-donor aspirins containing nitrooxy groups. They could represent an alternative to the use of aspirin in a variety of clinical applications.

The decomposition of peroxynitrite near neutral pH leads ultimately to the formation of dioxygen and nitrite via an intermediate with an absorbance maximum at 284 nm. The intermediate oxidises I(-) with a rate constant of (78 +/- 8) x 10 M(-1) s(-1) and decays near pH 7 with a rate constant of (0.58 +/- 0.02) s(-1) at 22 degrees C, but is longer-lived at lower pH. On the basis of experiments performed with a tandem-quenching flow reactor, we tentatively identify this intermediate as peroxynitric acid, formed during the proposed reaction sequence ONOOH + ONOO(-) --> NO(2)(-) + O(2)NOO(-) + H(+) --> 2 NO(2)(-) + O(2). These products are those expected from a peracid. The rate constant for the first reaction is ca. 3 x 10(4) M(-1) s(-1). Part of the dioxygen formed is in the (1)Delta(g) state (S. Miyamoto, G. E. Ronsein, T. C. Corréa, G. R. Martinez, M. H. G. Medeiros and P. Di Mascio, Dalton Trans., 2009, DOI: 10.1039/b905560f). The decay of peroxynitrous acid at concentrations higher than 0.1 mM near neutral pH is best described by the simultaneous process of isomerisation (k = 1.2 s(-1)) and decomposition to peroxynitrate. The rate of formation and the amount of peroxynitrate formed are much larger than can be accounted for by homolysis reactions.

Mechanistic investigations of biological enzymatic processes require controlled initiation and monitoring of catalytic reactions. A well-known technique to trap and observe reaction intermediates building up along a reaction pathway is the use of low temperature conditions. Here, we report a kinetically competent system for the release of molecular oxygen at cryogenic temperature, using a cobalt-based caged oxygen molecule, (micro-peroxo)(micro-hydroxo)bis[bis(bipyridyl)cobalt(III)] nitrate. Cryophotolysis of this compound was induced using 266 nm laser light and monitored by absorption microspectrophotometry. Furthermore, to verify that photo-fragmentation was accompanied by release of the active caged molecule, the production of dioxygen during cryophotolysis was directly visualized. This work lays the foundations for the use of low temperature reaction triggering as a tool to prolong the lifetime of normally unstable intermediate states in oxygen-dependent enzymes.

Synthesis and structural characterization of the 4-phenylbutane-1,2-diyl dinitrate and of the erythro and threo diastereoisomers of 4-phenylbutane-1,2,3-triyl trinitrate as well as the HPLC chiral separation of the corresponding racemic mixtures are reported. Vasodilator activity of the single enantiomers of these products, of 4-phenylbutyl nitrate, and of the previously described phenylpropyl analogues were assessed on rat aorta strips precontracted with phenylephrine. The compounds were able to relax the contracted tissue in a concentration dependent manner. In the couples of antipodes, a complete lack of enantioselectivity was observed as far as the vasodilator potency is concerned. The concentration response curves of the products, with the exception of those of all the trinitrooxy substituted models, were rightward shifted in the presence of ALDH-2 inhibitors. Mono and dinitrates, but not trinitrates, displayed in vitro cross-tolerance with GTN. This new series of nitric acid esters is an interesting tool that can help to shed light on the unresolved puzzle of nitrate pharmacology. Selected members are worthy of additional study as potential drugs.

Glutathione reductase (GR), is responsible for the existence of GSH molecule, a crucial antioxidant against oxidative stress reagents. The antimalarial activities of some redox active compounds are attributed to their inhibition of antioxidant flavoenzyme glutathione reductase, and inhibitors are therefore expected to be useful for the treatment of malaria. Twelve organic nitrate derivatives were synthesized and treated with human erythrocyte GR. The molecules were identified as strong GR inhibitors and novel antimalaria candidates.

Glycerol esters 1,3-dinitrates of the cyclooxygenase metabolites of natural prostaglandin 2-arachidonoylglycerol, an endogenous ligand of cannabinoid receptors, were synthesized for the first time. Four methods of synthesis of these esters were developed via the activation of a carboxyl group and their chemical and pharmacological properties were investigated. The esters exhibit a more selective pharmacological spectrum of activities in comparison with the corresponding natural prostaglandins: some types of myotropic activity were enhanced, while others were loosened. 1,3-dinitroglycerol esters act as vasodilators, whereas the majority of natural prostaglandins act as vasoconstrictors. The observed changes result from the introduction of an NO-releasing fragment into prostaglandin molecule.

Two types of new chrysin derivatives were prepared by coupling NO donors of alkyl nitrate and furazan derivatives and were fully characterized by (1)H NMR and other techniques. These compounds were tested in human umbilical vein endothelial cells (HUVECs-12) and all the compounds exhibited cell proliferation. Notable effects of promoting angiogenesis were observed for all the modified compounds using chick chorioallantoic membrane (CAM) assay.

This paper describes the preparation of [Cu(bh)2(H2O)2](NO3)2], [Cu(ibh)2(NO3)2], [Cu(ibh)2(H2O)2](NO3)2 and [Cu(iinh)2(NO3)2] (bh = benzoyl hydrazine (C6H5CONHNH2); ibh = isonicotinoyl hydrazine (NC5H4CONHNH2); ibh = isopropanone benzoyl hydrazone (C6H5CONHN=C(CH3)2; iinh = isopropanone isonicotinoyl hydrazone (NC5H4CONHN=C(CH3)2). These copper(II) complexes are characterized by elemental analyses, molar conductances, dehydration studies, ESR, IR and electronic spectral studies. The electronic and ESR spectra indicate that each complex exhibits a six-coordinate tetragonally distorted octahedral geometry in the solid state and in DMSO solution. The ESR spectra of most of the complexes are typically isotropic type at room temperature (300 K) in solid state as well as in DMSO solution. However, all the complexes exhibit invariably axial signals at 77 K in DMSO solution. The trend g(||) > g(perpendicular) > g(e,) observed in all the complexes suggests the presence of an unpaired electron in the d x2-y2 orbital of the Cu(II). The bh and inh ligands bond to Cu(II) through the >C=O and -NH2 groups whereas, ibh and iinh bond through >C=O and >C=N- groups. The IR spectra of bh and ibh complexes also show H-O-H stretching and bending modes of coordinated water.

Ammonium nitrate and calcium ammonium nitrate are the most commonly used straight nitrogen fertilisers in Europe, accounting for 43% of the total nitrogen used for fertilisers. They are both produced in a similar way; carbonate can be added as a last step to produce calcium ammonium nitrate. The environmental impact, fossil energy input and land use from using gasified biomass (cereal straw and short rotation willow (Salix) coppice) as feedstock in ammonium nitrate production were studied in a cradle-to-gate evaluation using life cycle assessment methodology. The global warming potential in the biomass systems was only 22-30% of the impact from conventional production using natural gas. The eutrophication potential was higher for the biomass systems due to nutrient leaching during cultivation, while the acidification was about the same in all systems. The primary fossil energy use was calculated to be 1.45 and 1.37MJ/kg nitrogen for Salix and straw, respectively, compared to 35.14MJ for natural gas. The biomass production was assumed to be self-supporting with nutrients by returning part of the ammonium nitrate produced together with the ash from the gasification. For the production of nitrogen from Salix, it was calculated that 3914kg of nitrogen can be produced every year from 1ha, after that 1.6% of the produced nitrogen has been returned to the Salix production. From wheat straw, 1615kg of nitrogen can be produced annually from 1ha, after that 0.6% of the nitrogen has been returned.

Reaction of nitrate radicals, NO*3 , with aromatic amino acids leads to irreversible oxidative functionalization at the beta-position or at the aromatic ring, suggesting that this important atmospheric oxidant could potentially cause damage to peptides lining the respiratory tract and may contribute to pollution-derived diseases.

The paper presents the results of laboratory and pilot studies on the removal of chloramine from potable water using chlorination with a less-than-breakpoint dosage of chlorine, followed by treatment with catalytic activated carbon. The effect of the chlorine-to-nitrogen ratio, temperature, and carbon contact time were investigated to optimize conditions for chloramines removal and minimize the production of ammonia. Results demonstrated that prechlorination of water, followed by treatment with catalytic activated carbon, can degrade monochloramine to nitrogen gas as a main product. For all chlorine-to-ammonia ratios studied, the observed rates of monochloramine removal were higher at a temperature of 20 degrees C than they were at 5 degrees C. Generation of ammonia was slightly higher at the lower temperature. However, at both temperatures, practically all monochloramine was destroyed, and only insignificant amounts of ammonia were formed when a chlorine-to-ammonia ratio of 7:1 was applied. The described method is simple and cost-effective, because it eliminates the requirement of removal of ammonia, typically formed during the treatment of chloramines with activated carbon.

The present work aims at developing a new process to synthesize HMX from DAPT using ultrasound in ionic liquid. Reaction has been carried out in ultrasonic bath, effect of various parameters such as presence and absence of ultrasound, volume and type of solvent, temperature, concentration of nitrating agent has been investigated with an aim of obtaining the optimum conditions for the synthesis of HMX. It was observed that ultrasonically promoted nitroylsis of DAPT to HMX has exhibited significant enhancement in yield at ambient condition.

Posttranslational protein tyrosine oxidation, to yield 3-nitrotyrosine, is a biologically relevant protein modification related with acute and chronic inflammation and degenerative processes. It is usually associated with a decrease or loss in protein function. However, in some proteins, tyrosine nitration results in an increase or gain in protein function. Nitration of cytochrome c by biological oxidants in vitro can be achieved via different mechanisms, which include reactions with peroxynitrite, nitrite plus hydrogen peroxide, and nitric oxide plus hydrogen peroxide, and result in a loss in its electron transport capacity and in a higher peroxidatic activity. This chapter describes the methodology for studying chemical and biological properties of nitrocytochrome c. In particular, we report methods to synthesize tyrosine-nitrated cytochrome c, purify cytochrome c mononitrated species, map the sites of tyrosine nitration, and investigate the functional consequences of nitrated cytochrome c on mitochondrial electron transport properties, peroxidatic activity, and apoptosome assembly.

The effect of gas bubbling on the removal efficiency of 4-chlorophenol (4-CP) in aqueous solution has been investigated using a novel pulsed high voltage gas-liquid hybrid discharge reactor, which generates gas-phase discharge above the water surface simultaneously with the spark discharge directly in the liquid. The time for 100% of 4-CP degradation in the case of oxygen bubbling (7 min) was much shorter than that in the case of nitrogen bubbling (25 min) as plenty of hydrogen peroxide and ozone formed in oxygen atmosphere enhanced the removal efficiency of 4-CP. Except for the main similar intermediates (4-chlorocatechol, hydroquinone and 1,4-benzoquinone) produced in the both cases of oxygen and nitrogen bubbling, special intermediates (5-chloro-3-nitropyrocatechol, 4-chloro-2-nitrophenol, nitrate and nitrite ions) were produced in nitrogen atmosphere. The reaction pathway of 4-CP in the case of oxygen bubbling was oxygen/ozone attack on the radical hydroxylated derivatives of 4-CP. However, in the case of nitrogen bubbling, hydroxylation was the main reaction pathway with effect of N atom on degradation of 4-CP.