A nitric oxide-releasing polydiazeniumdiolate derived from acetonitrile

Acetonitrile, frequently used as a solvent in reactions of nitric oxide (NO) with amines and other nucleophiles to introduce the [N(O)NO](-) (diazeniumdiolate) functional group, has itself been shown to react with NO in the presence of strong base to yield methane trisdiazeniumdiolate (1), presumably via an intermediate trisdiazeniumdiolated imidate. Aqueous hydrolysis of 1 does not follow simple first-order kinetics and produces mixtures of NO and nitrous oxide in ratios that vary with solution pH. [reaction: see text]     

Water-soluble nitric oxide-releasing gold nanoparticles

The synthesis and characterization of water-soluble nitric oxide (NO)-releasing monolayer-protected gold clusters (MPCs) are reported. Tiopronin-protected MPCs ( approximately 3 nm) were functionalized with amine ligands and subsequently exposed to 5 atm of NO to form diazeniumdiolate NO donors covalently bound to the gold MPC. Diazeniumdiolate formation conditions, NO-release, and nanoparticle stability were examined as a function of the structure of the protecting ligand, pH, and storage time. Despite their aqueous solubility, proton-initiated decomposition of the diazeniumdiolate-modified Tio-MPCs resulted in only modest NO-release (<0.023 micromol/mg) for short durations (<1.5 h). To increase the NO storage capacity of gold nanoparticles, polyamine-stabilized MPCs ( approximately 5 nm) were synthesized with significantly enhanced NO-release properties (0.386 micromol/mg) and durations (up to 16 h). Transmission electron microscopy, thermogravimetric analysis, nuclear magnetic resonance spectroscopy, elemental analysis, and UV-vis spectroscopy were used to characterize both nanoparticle systems before and after NO exposure. The MPCs represent the smallest water-soluble NO-release nanoparticles to date (3-5 nm).     

Synthesis of nitric oxide-releasing silica nanoparticles

The synthesis and characterization of a new nitric oxide (NO)-releasing scaffold prepared from amine-functionalized silica nanoparticles are reported. Inorganic-organic hybrid silica was prepared via cocondensation of tetraethoxy- or tetramethoxysilane (TEOS or TMOS) and aminoalkoxysilane with appropriate amounts of ethanol (or methanol), water, and ammonia. The amine functional groups in the silica were converted to N-diazeniumdiolate NO donors via exposure to high pressures of NO (5 atm) under basic conditions. Control over both the structure and concentration of the silane precursors (i.e., tetraalkoxy- and aminoalkoxysilanes) and specific synthetic conditions allowed for the preparation of NO donor silica particles of widely varying sizes (d = 20-500 nm), NO payloads (50-1780 nmol.mg-1), maximum amounts of NO released (10-5500 ppb.mg-1), half-lives (0.1-12 h), and NO release durations (up to 30 h). The silica nanoparticles were characterized by solid-state 29Si nuclear magnetic resonance (NMR), atomic force microscopy (AFM), elemental analysis, and gas adsorption-desorption isotherms. The advantages of silica-derived NO storage/delivery systems over previously reported macromolecular NO donors include the ability to (1) store large quantities of NO, (2) modulate NO release kinetics, and (3) readily tune particle size based on the composition of the particle. In addition, a one-pot strategy for preparing the NO donor silica allows for straightforward, high-throughput synthesis and purification.     

Synthesis of nitric oxide-releasing gold nanoparticles

We report the synthesis of nitric oxide-releasing gold nanoparticles formed by place-exchange reaction of hexanethiol monolayer-protected clusters with diamine nitric oxide donor precursor molecules, which are subsequently converted to N-diazeniumdiolate NO donors. The nitric oxide release from the N-diazeniumdiolate-modified gold nanoparticles is tunable by varying the number and/or the chemical structure of the exchanged amine ligands. The size and stability of NO-releasing nanoparticles may prove useful for a range of biomedical and pharmaceutical applications.     

Advances in nitric oxide-releasing hydrogels for biomedical applications

Hydrogels provide a plethora of advantages to biomedical treatments due to their highly hydrophilic nature and tissue-like mechanical properties. Additionally, the numerous and widespread endogenous roles of nitric oxide have led to an eruption in research developing biomimetic solutions to the many challenges the biomedical world faces. Though many design factors and fabrication details must be considered, utilizing hydrogels as nitric oxide delivery vehicles provides promising materials in several applications. Such applications include cardiovascular therapy, vasodilation and angiogenesis, antimicrobial treatments, wound dressings, and stem cell research. Herein, a recent update on the progress of NO-releasing hydrogels is presented in depth. In addition, considerations for the design and fabrication of hydrogels and specific biomedical applications of nitric oxide-releasing hydrogels are discussed.     

Synthesis and characterization of nitric oxide-releasing sol-gel microarrays

Diazeniumdiolate-modified sol-gel microarrays capable of releasing low levels of nitric oxide are reported as a viable means for improving the blood compatibility of a surface without fully modifying the underlying substrate. Several parameters are characterized including: (1) NO surface flux as a function of sol-gel composition and microarray geometry; (2) microstructure dimensions and spacing for optimal blood compatibility; and (3) the effect of sol-gel surface modification on analyte accessibility to platinum electrodes. The sol-gel microarrays release biologically relevant levels of NO under physiological conditions for >24 h. In vitro platelet adhesion assays indicate that a NO surface flux of 2.2 pmol cm(-2) s(-1) effectively reduces platelet adhesion to glass substrates modified with sol-gel microstructures separated by 50 microm. The blood compatibility observed for these micropatterned surfaces is comparable to NO-releasing sol-gel films. When the separation between NO-releasing microstructures is reduced to 10 microm, the NO surface flux required to reduce platelet adhesion is lowered to 0.4 pmol cm(-2) s(-1). Finally, the oxygen response of platinum electrodes modified with NO-releasing sol-gel microarrays indicates that selective modification via micropatterning enhances analyte accessibility to the sensor surface.     

Synthesis and bioactivity of novel nitric oxide-releasing ursolic acid derivatives

A series of furoxan-based novel nitric oxide-donating ursolic acid(UA) derivatives(7a-f) were synthesized,and their cytotoxic activities against HepG2 cells in vitro were evaluated by MTT method.It was found that 7a-d and 7f showed more potent cytotoxic activities than control 5-fluorouracil and UA.     

NO-NSAIDs. Part 3: nitric oxide-releasing prodrugs of non-steroidal anti-inflammatory drugs

In continuation of our efforts to discover novel nitric oxide-releasing non-steroidal anti-inflammatory drugs (NO-NSAIDs) as potentially "Safe NSAIDs," we report herein the design, synthesis and evaluation of 21 new NO-NSAIDs of commonly used NSAIDs such as aspirin, diclofenac, naproxen, flurbiprofen, ketoprofen, sulindac, ibuprofen and indomethacin. These prodrugs have NO-releasing disulfide linker attached to a parent NSAID via linkages such as an ester (compounds 9-16), a double ester (compounds 17-24), an imide (compounds 25-30) or an amide (compounds 31-33). Among these NO-NSAIDs, the ester-containing NO-aspirin (9), NO-diclofenac (10), NO-naproxen (11), and the imide-containing NO-aspirin (25), NO-flurbiprofen (27) and NO-ketoprofen (28) have shown promising oral absorption, anti-inflammatory activity and NO-releasing property, and also protected rats from NSAID-induced gastric damage. NO-aspirin compound 25, on further co-evaluation with aspirin at equimolar doses, exhibited comparable dose-dependent pharmacokinetics, inhibition of gastric mucosal prostaglandin E(2) (PGE(2)) synthesis and analgesic properties to those of aspirin, but retained its gastric-sparing properties even after doubling its oral dose. These promising NO-NSAIDs could therefore represent a new class of potentially "Safe NSAIDs" for the treatment of arthritic pain and inflammation.     

Synthesis and biological evaluation of nitric oxide-releasing matrine derivatives as anticancer agents

<正>A series of furoxan-based nitric oxide-releasing matrine derivatives(10a-f) were synthesized.The biological evaluation showed that compounds 10a,10b,10e and 10f had stronger cytotoxic activities than 5-fluorouracil against human hepatoma cells(HepG2) in vitro.     

Synthesis and biological evaluation of nitric oxide-releasing sixalkoxyl biphenyl derivatives as anticancer agents

A series of novel nitric oxide-donating sixalkoxyl biphenyl derivatives （14a-1） were synthesized by coupling furoxan with alkoxyl biphenyl skeleton using amino acids as the spacers, and their cytotoxicity against HepG2 cells in vitro were evaluated by MTT method. It was found that 14c, 14d, 14f, 14i, 14j and 14k showed more potent cytotoxic activities than control 5-fluorouracil. NO release assay of target compounds indicated that the maximum amount of NO released by most active compounds 14c and 14j was about 6 × 10^-2 μmol/L, whereas 14a and 14h with very weak activity only released NO of 1 × 10^-2 μmol/L.     

Nitric oxide-releasing/generating polymers for the development of implantable chemical sensors with enhanced biocompatibility

This paper reports a derivatization, mass fragmentation study relating to the most common, non-steroidal anti-inflammatory drugs (NSAIDs), such as ibuprofen, naproxen, ketoprofen and diclofenac, identified and quantified in the aquatic environment. Derivatizations have been performed with four silylation reagents in order to select the most proper one, taking into account analytical and financial points of view, equally. The tested reagents were N,O-bis(trimethylsilyl)trifluoroacetamide (BSTFA), N-methyl-N-(trimethylsilyl)trifluoroacetamide (MSTFA), N-methyl-N-tert-butyldimethylsilyl-trifluoroacetamide (MTBSTFA) and for this purpose at the first time, hexamethyldisilazan (HMDS)+trifluoroacetic acid (TFAA). Varying derivatization time and temperature, taking into consideration chemical and financial advantages, HMDS+TFAA proved to be the optimum selection. Responses of derivatives have been compared, as a function of the ionization technique (external/internal ionization), as well as on the treatment of compounds' selective fragment ions (SFIs): (i) extracting the corresponding, characteristic m/z masses from TIC elutions and (ii) from SIM elutions, in parallel. Reproducibilities of measurements, expressed in relative standard deviation percentages (R.S.D.%), including the nanogram and the low picogram levels of injected derivatives, provided an average between 0.93 R.S.D.% and 4.11 R.S.D.%. NSAIDs' enrichment was performed with solid-phase extraction (SPE), applying the Oasis HLB (Waters) cartridges: recoveries in the 1-6 microg L(-1) range varied between 84% and 111%, with an average reproducibility of 6.4 R.S.D.%. The utility of the optimized derivatization method is presented, on monthly basis, by the identification and quantitation of the ibuprofen, naproxen, ketoprofen and diclofenac content of the influent and effluent waste-water samples obtained from a Hungarian waste-water treatment plant.     

High-temperature oxygen sensors for glass-forming melts

Electrochemical sensors are reported for the on-line measurement of oxygen partial pressures of oxidic glass-forming melts on a laboratory and technical scale. Based on the principle of solid electrolyte cells without transference, they are principally simple units. The extreme chemical and temperature conditions of their applications, however, demanded extensive fundamental investigations and resulted in specific forms of reference and measuring electrodes, a thermo-dynamic procedure of verifying the correct functioning of such cells, and a method of measuring thermoelectric voltages of non-isothermal glass melts.     

Iridium luminophore complexes for unimolecular oxygen sensors

In this study, a series of novel luminescent cyclometalated Ir(III) complexes has been synthesized and evaluated for use in unimolecular oxygen-sensing materials. The complexes Ir(C6)(2)(vacac), 1, Ir(ppy)(2)(vacac), 2, fac-Ir(ppy)(2)(vppy), 3, and mer-Ir(ppy)(2)(vppy), 4, where C6 = Coumarin 6, vacac = allylacetoacetate, ppy = 2-phenylpyridine, and vppy = 2-(4-vinylphenyl)pyridine, all have pendent vinyl or allyl groups for polymer attachment via the hydrosilation reaction. These luminophore complexes were characterized by NMR, absorption, and emission spectroscopy, luminescence lifetime and quantum yield measurements, elemental analysis, and cyclic voltammetry. Complex 1 was structurally characterized using X-ray crystallography, and a series of 1-D ((1)H, (13)C) and 2-D ((1)H-(1)H, (1)H-(13)C) NMR experiments were used to resolve the solution structure of 4. Complexes 1 and 3 displayed the longest luminescence lifetimes and largest quantum efficiencies in solution (tau = 6.0 micros, phi = 0.22 for 1; tau = 0.4 micros, phi = 0.2 for 3) and, as result, are the most promising candidates for future luminescence-quenching-based oxygen-sensing studies.     

Synthesis and biological evaluation of novel furozan-based nitric oxide-releasing derivatives of oridonin as potential anti-tumor agents

To search for novel nitric oxide (NO) releasing anti-tumor agents, a series of novel furoxan/oridonin hybrids were designed and synthesized. Firstly, the nitrate/nitrite levels in the cell lysates were tested by a Griess assay and the results showed that these furoxan-based NO-releasing derivatives could produce high levels of NO in vitro. Then the anti-proliferative activity of these hybrids against four human cancer cell lines was also determined, among which, 9 h exhibited the most potential anti-tumor activity with IC?? values of 1.82 μM against K562, 1.81 μM against MGC-803 and 0.86 μM against Bel-7402, respectively. Preliminary structure-activity relationship was concluded based on the experimental data obtained. These results suggested that NO-donor/natural product hybrids may provide a promising approach for the discovery of novel anti-tumor agents.     

Sol-gel derived oxides and mixed oxides catalysts with narrow mesoporous distribution

A novel sol-gel process for preparing oxides and mixed oxides sols from precipitation and peptization process is reported in this article. Inorganic salts are used as raw materials in this study. It is found that the amount of acid has great influence on the stability and particle diameter distribution of the precursor sols. Ultrasonic treatment is used to prepare alumina sol at room temperature. The result of 27AI NMR shows that there exist AI_13~(7+) species in the sol. By controlling the sol particles with narrow particle diameter distribution, alumina, titania and silica-alumina (SA) materials with narrow mesoporous distribution are formed by regular packing of sol particles during gelation without using any templates. The results also show that the structure and particle diameter distribution of precursor sol determine the final materials' texture.     

Synthesis and in vitro biological evaluation of nitric oxide-releasing derivatives of hydroxylcinnamic acids as anti-tumor agents

Novel furoxan-based nitric oxide-releasing derivatives 6a-p of hydroxylcinnamic acids were synthesized by coupling the carboxyl group of hydroxylcinnamic acids with furoxan through various alkylol amines. Compounds 6a, e-i and m-p displayed more potent anti-tumor activities superior to control 5-fluorouracil (5-FU) in most cancer cells tested. Furthermore, 6f could selectively inhibit tumor cells, but not non-tumor cell proliferation. This inhibition was attributed to high levels of NO released in cancer cells and potentially synergistic effect of NO donor moieties and the bioactivity of hydroxylcinnamic acids.     

Aminotroponiminates as ligands for potential metal-based nitric oxide sensors

A family of new fluorescently labeled ligands, HRDATI, was prepared to develop transition-metal-based NO sensing strategies. The ligands are composed of aminotroponiminates (ATIs) with a dansyl fluorophore on one of the imine nitrogen atoms and an alkyl substituent, either i-Pr (8), t-Bu (9), or Bz (10), on the other. Bis(chelate) Co2+ ([Co(i-PrDATI)2] (12), [Co(t-BuDATI)2] (14), [Co(BzDATI)2] (15)) and Zn2+ ([Zn(i-PrDATI)2] (13)) complexes were prepared and characterized by X-ray crystallography. The bis(ATI) complex [Co(i-Pr2ATI)2] (11) was also prepared and its X-ray crystal structure determined. Cyclic voltammetry reveals reversible redox waves at -2.57 and -0.045 V (vs Cp2Fe/Cp2Fe+) in THF for the Co2+/Co+ and Co3+/Co2+ couples, respectively, of 11. Only a Co2+/Co+ wave at -2.09 V is observed for 12. When excited at 350 nm, the HRDATI ligands and the diamagnetic Zn2+ complex 13 fluoresce around 500 nm, whereas the paramagnetic Co2+ complexes quench the fluorescence. These air-stable cobalt compounds react with nitric oxide to dissociate a DATI ligand and form neutral dinitrosyl complexes, [Co(NO)2(RDATI)]. The release of the fluorophore-containing ligand is accompanied by an increase in fluorescence intensity, thus providing a strategy for fluorescent NO sensing. Linking two DATI moieties via a tetramethylene chain affords the ligand H2DATI-4 (18). The Co2+ complex [Co(DATI-4)] (19) reacts more readily with NO than the bis(DATI) compounds and also displays an increase in fluorescence intensity upon NO binding.