In vitro, ex vivo and in vivo short-term screening of DHEA nitrate derivatives activity over Trypanosoma cruzi Ninoa and TH strains from Oaxaca State, México.

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-3ß,17ß-diol (4a), respectively. In addition, compounds 3a and 3b were obtained by introducing an α-ethynyl and a ß-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-3ß,17ß-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.

Recent Advances in Synthesis and Properties of Nitrated-Pyrazoles Based Energetic Compounds.

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.

Deep eutectic solvent-assisted facile synthesis of copper hydroxide nitrate nanosheets as recyclable enzyme-mimicking colorimetric sensor of biothiols.

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 (Cu2(OH)3NO3) 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 Cu2(OH)3NO3, 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.

Preparation of 6-aminocyclohepta-2,4-dien-1-one Derivatives via Tricarbonyl(tropone)iron.

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.

Design, Synthesis and Biological Evaluation of Nitrate Derivatives of Sauropunol A and B as Potent Vasodilatory Agents.

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.

Synthesis, hepatotoxic evaluation and antipyretic activity of nitrate ester analogs of the acetaminophen derivative SCP-1.

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.

Incorporation of nitric oxide donor into 1,3-dioxyxanthones leads to synergistic anticancer activity.

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 IC50 of 0.33 ±â€¯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.

Recent Developments in Drug Design of NO-donor Hybrid Compounds.

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.

Modeling of the Bioactivation of an Organic Nitrate by a Thiol to Form a Thionitrate Intermediate.

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.

Synthesis and anti-cancer potential of the positional isomers of NOSH-aspirin (NBS-1120) a dual nitric oxide and hydrogen sulfide releasing hybrid.

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.

Regioselective Green Electrochemical Approach to the Synthesis of Nitroacetaminophen Derivatives.

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.

Synthesis of 2-[(18)F]Fluoro-2-deoxyisosorbide 5-mononitrate and Assessment of Its in vivo Biodistribution as Determined by Dynamic Positron Emission Tomography (PET).

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.

Positional isomerism markedly affects the growth inhibition of colon cancer cells by NOSH-aspirin: COX inhibition and modeling.

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.

Synthesis, characterization and luminescent properties of lanthanide complexes with a novel multipodal ligand.

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.

Atmospheric formation of the NO3 radical from gas-phase reaction of HNO3 acid with the NH2 radical: proton-coupled electron-transfer versus hydrogen atom transfer mechanisms.

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.

Synthesis, growth and characterisations of semi-organic nonlinear optical crystal glycine barium nitrate (GBN).

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.

Criegee intermediates in the indoor environment: new insights.

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.

Changes in North Atlantic nitrogen fixation controlled by ocean circulation.

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.

NO-donating tacrine derivatives as potential butyrylcholinesterase inhibitors with vasorelaxation activity.

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.

Heterogeneous reaction of NO2 on Al2O3: the effect of temperature on the nitrite and nitrate formation.

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.