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The goal of present work is the study of NO releasing mechanisms in nitrofuroxanoquinoline (NFQ) derivatives. Mechanisms of their structural non-rigidity and pathways of NO donation - spontaneous or under the action of sulfanyl radicals or photoirradiation - were considered in details, both experimentally and quantum chemically. Furoxan-containing systems of the discussed type are not capable of spontaneous or photoinduced decomposition under mild conditions, and sulfanyl (radical) induced processes are the most preferable. It was shown that appropriate modification of NFQ through [3 + 2] cycloaddition and subsequent aromatization is a powerful tool to design new prospective donors of NO molecule. Two newly obtained NFQ derivatives were proven to have unusually high NO activity in full accordance with the theoretical model. We hope that these examples will encourage community to seek for new NO active molecules among cycloadducts and modified furoxanes., (Copyright © 2019 Elsevier Inc. All rights reserved.)

A water-soluble near-infrared aminocyanine dye has been developed with a long triplet-state lifetime (τ = 9.16 μs in deaerated ethanol). Thereby, extremely high singlet oxygen quantum yield (ΦΔ = 0.20) and low dark cytotoxicity (IC50 = 715.4 μM) were achieved. The potential of the dye as a PDT photosensitizer was demonstrated.

SN30000 is a benzotriazine di-N-oxide which is selectively toxic to radio-resistant hypoxic cells in tumours. Given the complex photochemistry of some aromatic N-oxides, we evaluated the potential for photodegradation of SN30000 solutions. Initial studies demonstrated significant oxygen-insensitive degradation under normal laboratory lighting conditions. The kinetics of photodegradation showed marked concentration dependence of the form predicted by Beer's law, with a quantum yield of 0.016. The photoproducts could be rationalised as arising from an oxaziridine intermediate. The major stable product (cmpd 6; yield ∼50% of SN30000 loss under either UV or visible light) was characterised as resulting from intra-molecular oxygen transfer to the morpholine side chain of SN30000. This mechanism is consistent with lack of formation of the corresponding morpholine N-oxide from an analogue (SN29751) in which the proposed six-membered-ring transition state cannot form. Cmpd 6 was less cytotoxic than SN30000 to human tumour cells in culture, under either hypoxic or aerobic conditions, and was not toxic when administered intra-peritoneally to NIH-III nude mice at a dose (750 μmol/kg) above the maximal tolerated dose of SN30000 itself. In conclusion, SN30000 solutions are significantly photosensitive at low concentration, requiring protection from light, but the major photoproduct is less toxic than the parent., (© 2014 Wiley Periodicals, Inc. and the American Pharmacists Association.)

We investigated the amount and distribution of hydrogen peroxide (H(2)O(2)) generated in a solid gelatin sample irradiated by heavy ion (carbon) beam. We irradiated the gelatin sample, which contained a nitroxyl radical (4-hydroxy-2,2,6,6-tetramethylpiperidine-N-oxyl, TEMPOL), with a 290-MeV/nucleon carbon beam (~128 Gy). To verify the distribution of H(2)O(2) generation in the irradiated sample, we employed both electron paramagnetic resonance (EPR) spectroscopic and magnetic resonance (MR) imaging methods based on H(2)O(2)-dependent paramagnetic loss of TEMPOL. We obtained a distribution profile of the H(2)O(2)-dependent reaction in the gelatin sample when we irradiated gelatin samples with carbon beams with several different linear energy transfer (LET) values. Because the profiles of oxygen consumption in the gelatin sample measured by L-band EPR oxymetry and of the H(2)O(2)-dependent reaction have almost the same shape, the profile of the H(2)O(2)-dependent reaction can be used as an estimation of the profile of the generation of H(2)O(2). The H(2)O(2) profile in one intact gelatin sample scanned by 7-tesla MR imaging showed a similar shape as a result of the EPR experiment. We obtained several hundreds of micromolars of H(2)O(2) generated in a gelatin sample irradiated by carbon beam when 200 Gy was given at the surface of the sample. H(2)O(2) distribution was almost flat, with only a slight peak just before the end of the beam.

We performed mechanistic studies of the reaction of PBN with the physiologically relevant glutathiyl radical, GS*, formed upon oxidation of the intracellular antioxidant, glutathione, GSH. The scavenging rate constant of GS* by PBN has been measured directly by laser flash photolysis and indirectly by competitive EPR of the spin adduct of PBN and another spin trap, DMPO (5,5-dimethyl-1-pyrroline N-oxide), and was found to be 6.7 x 107 M(-1) s(-1). Reverse decomposition of the paramagnetic PBN-glutathiyl radical adduct to the nitrone and thiyl radical was observed for the first time. The rate constant for the reaction of the monomolecular decomposition of the radical adduct was found to be 1.7 s(-1). Diamagnetic, EPR-invisible products of PBN adduct degradation were studied by 1H NMR and 19F NMR using newly synthesized fluorine-substituted PBN.

When using ESR to measure the radicals generated by ultrasound, it is necessary to extract a solution and place it in the ESR system. To avoid this process, we incorporated an ultrasonic reaction cell in an L-band ESR-CT system, producing a system that allows the detection of the concentration of radicals during ultrasonic irradiation. This system was used to measure the time and space dependences of OH radicals generated by ultrasonic irradiation. When a 10 ml aqueous solution of 1-hydroxy-2,2,5,5-tetramethyl-3-imidazoline-3-oxide (HTIO) was irradiated with ultrasound, it was found that the generation of radicals was clearly shown in a CT image after a period of 10 min. It was also found that continued irradiation resulted in an increased concentration of radicals. In addition to this system, an X-band ESR system was also used to measure the concentration of OH radicals generated, and the results of both systems were then compared. Both results are very similar, showing that the proposed system, which was realized by incorporating an ultrasonic irradiation cell in the L-band ESR-CT system, operated properly. Because this system allows the measurement of sonochemical reactions in an opaque cell or an opaque solution such as blood and industrial wastewater, it is a very useful measurement system for achieving the applying of sonochemistry to the medical engineering field.

We predict the photoswitching magnetic properties of four substituted dihydropyrenes from density functional broken-symmetry calculations. The magnetic exchange coupling constants differ up to 9.44 cm(-1). The intramolecular exchange interactions are ferromagnetic in nature. The calculated coupling constants are much larger than those reported earlier for photomagnetic organic molecules.

The exposure of 4-hydroxy-2,2,6,6-tetramethylpiperidine-N-oxyl (TEMPOL) to hydroxyl radical ((.)OH) led to the appearance of a new triplet ESR signal along with a reduction in the intensity of the TEMPOL signal. The observed spectrum was in good agreement with the spectrum simulated with 4-oxo-2,2,6,6-tetramethylpiperidine-N-oxyl (TEMPON) and TEMPOL, and the addition of sodium borohydride to the product solution led to the disappearance of the new signal. These results indicate the formation of TEMPON during the reaction. A comparison of the concentration of TEMPON formed with that of nitroxyl compounds that lost the electron spin resonance (ESR) signal showed that the rate of TEMPON formation is less than one-tenth that of the paramagnetism loss caused by (.)OH in the pH range 6.5-8.5. These results indicate that TEMPOL has two reaction sites with (.)OH; the nitroxyl group and the 4-position of the piperidine ring. The reaction at the 4-position should contribute to the (.)OH scavenging activity of TEMPOL together with that at the nitroxyl group, although the rate of the former reaction is relatively low., (Copyright 2003 Wiley-Liss, Inc. and the American Pharmaceutical Association J Pharm Sci 92:275-280, 2003)

The photodegradation of fluchloralin by UV irradiation or sunlight in aqueous methanolic solution has been examined. In the presence of titanium dioxide five photoproducts were obtained, but only four in its absence. One photoproduct, 2, 2'-azoxy-bis(alpha,alpha,alpha-trifluoro-6-nitro-p-toluidine) is reported for the first time as a metabolite of fluchloralin. In natural sunlight the rate of degradation was higher than in UV light and titanium dioxide had almost no effect on the rate of degradation.

Chemicals that upon absorption of light generate hydroxyl radicals (.OH), free of other damaging species under physiological conditions, are useful tools for the study of the biological effects of .OH radical and for its utilization for analytical purposes. We report the novel property of 2-methyl-4-nitro-quinoline-N-oxide (MNO) and 4,4'-dinitro-(2,2')bipyridinyl-N,N'-dioxide (DBD) to act as photogenerators of .OH with UV and visible light. Upon irradiation with 360-400 nm light MNO and DBD generate free radicals that convert coumarin carboxylic acid (CCA) to fluorescent 7-OH-CCA; the .OH radical scavengers dimethylsulfoxide (DMSO) and ethanol eliminate the induction of 7-OH-CCA fluorescence. Upon 400 nm illumination in the presence of MNO, supercoiled plasmid DNA is converted to circular and strand breakage is significantly reduced in the presence of DMSO and completely absent in the absence of MNO. The conversion of CCA to 7-OH-CCA and of supercoiled plasmid to circular DNA are also observed in the absence of oxygen. Taken together, these data indicate that MNO and DBD constitute novel .OH-generating compounds. Because currently known .OH-photogenerating compounds require UV illumination (< 360 nm) that also damages DNA and cells directly, the property of MNO to generate .OH upon 400 nm illumination is advantageous when studies on cells, DNA and other biomolecules are conducted.

The photolyses of phosphate-buffered (pH 7) air- and nitrogen-saturated solutions containing the water-soluble quinones, 1,4-benzoquinone (BQ), 2-methyl-1,4-benzoquinone (MBQ), sodium 1,4-naphthoquinone-2-sulfonate (NQ2S), 9,10-anthraquinone-2-sulfonate (AQ2S) or 9,10-anthraquinone-1,5-disulfonate (AQDS), and the spin trap 5,5-dimethylpyrroline-1-oxide (DMPO) produce a DMPO-OH adduct. Electron paramagnetic resonance spectroscopy of the photolyzed samples in 17O-enriched water demonstrates that this adduct derives almost exclusively from water. With the exception of BQ, quantum yields for the formation of DMPO-OH are larger in air than in nitrogen-saturated samples, thus supporting the idea of the formation of air-oxidized intermediates that enhance the DMPO hydroxylation reaction rate. Evidence has been obtained which suggests that BQ and MBQ, but not AQDS, are able to photooxidize water, with the consequent production of the free OH radical.

The production of 5,5-dimethyl-1-pyrroline-N-oxide (DMPO)/.OH in aqueous solutions of menadione and DMPO is enhanced by fluorescent room light. The formation of DMPO/.OH requires oxygen and water, is enhanced by superoxide dismutase, and occurs to a much smaller extent for benzoquinone than for menadione. This process is assigned as photo-initiated redox cycling of the menadione, which causes oxidation of DMPO to DMPO+. and reduction of oxygen to superoxide. DMPO+. reacts with water to produce DMPO/.OH. Although DMPO/.OOH was not observed in the menadione solutions, the possibility that some of the DMPO/.OH was produced by decomposition of DMPO/.OOH cannot be ruled out. There is no evidence for participation of hydroxyl radicals. Because benzosemiquinone is less readily oxidized than the semiquinone of menadione, redox cycling is less favorable for benzoquinone than for menadione and smaller quantities of DMPO/.OH are produced by photoexcitation of benzoquinone than of menadione.

The photosensitizing properties of p-nitroacetophenone (PNAP), a well-known radiosensitizer, have been studied in near UV region. The mechanism of PNAP photosensitization has been investigated by testing the efficiency of singlet oxygen production using photooxidation of 2,2,6,6-tetramethylpiperidine (TEMP) and photodegradation of guanosine. In both the cases, the enhancement effect of deuterated solvents has been observed. Results of these experiments suggest the significant role of type II mechanisms in PNAP photosensitization.

The efficiency of 5,5-dimethylpyrroline-1-N-oxide (DMPO) and alpha-(4-pyridyl-1-oxide)-N-tert.-butylnitrone (POBN) to spin trap hydroxyl radicals and hydrogen atoms, respectively, was studied in gamma-irradiated solutions where the radical yields are accurately known. The effects of dose, spin trap concentration, and pH and of the stability of the spin adducts on the spin-trapping efficiency were investigated. In degassed or N2-saturated solutions the spin-trapping efficiencies were 35% for DMPO and hydroxyl radicals and 14% for POBN and hydrogen atoms. The low spin-trapping efficiencies were shown not to be due to the instability of the DMPO-OH and POBN-H spin adducts or to the effects of H2O2 or O2. The low spin-trapping efficiency of DMPO may be explained by the reaction of hydroxyl radicals to abstract hydrogen from the DMPO molecule to produce carbon radicals as well as addition to the N = C double bond to form nitroxide radicals. For POBN the low spin-trapping efficiency for hydrogen atoms is explained in terms of addition reactions of hydrogen atoms to the aromatic ring and the pyridinium and nitrone oxygens.

The influence of solubilisation upon the reactivity of the nitroxyl BAPO with the free radicals produced in irradiated vesicle systems was investigated. The decomposition yield G(-BAPO) determined in didodecyldimethyl-ammonium bromide (DDAB) vesicle systems was found to be only 0.04, while in homogeneous aqueous solutions a value of 1.50 was observed. These results, as well as the EPR spectra of irradiated and nonirradiated samples, lead to the conclusion that BAPO is localized in the interior of the bilayer. This behavior is consistent with the hydrophobic character of the nitroxyl molecule due to its benzylidene group.

The mechanism of the gamma-radiolysis of the free nitroxyl radicals BAPO and CATPO in neutral deaerated as well as in N2O-saturated aqueous solutions was investigated. The decomposition of BAPO and CATPO was followed spectrophotometrically by measuring the absorbance at 249 and 233 nm, respectively. The yields G(-BAPO) and G(-CATPO) observed under several conditions are reported and discussed in relation to the yield of OH radicals, H atoms and e-aq, produced in irradiated aqueous solutions. It was found, on the analogy of other nitroxyls, that the corresponding hydroxylamines were formed when BAPO and CATPO react with H atoms, e-aq and hydroxyalkyl radicals. The H atoms and e-aq also react partly with BAPO and CATPO by addition to the aromatic nucleus and by elimination of NH3, respectively. The OH radicals react with BAPO by addition to the aromatic nucleus and by abstraction of H atoms from the 3 or 5 positions or from the methyl groups of the 2 or 6 positions. The reaction of OH radicals with CATPO consists in the abstraction of H atoms from the 3 or 4 positions or from the methyl groups of the 2 or 5 positions. The EPR spectra suggest that in both nitroxyls the final radiolysis products are stable biradicals and other paramagnetic compounds.

The reactions of free and DNA-bound 2,2,5,5-tetramethylpyrrolidine-N-oxyl (PROXYL) probes with radicals generated during radiolysis of dilute aqueous solutions of DNA were examined. For the free PROXYL probe in deaerated solution with each of the four nucleotides (dAMP, dCMP, dGMP, and TMP) it was found that the pyrimidine radicals were more reactive toward the probe than were the purine radicals. Reactions of the electron adduct of TMP and the hydroxyl radical adducts of dAMP, dGMP, and TMP with the probe resulted in little or no reduction of the probe. For TMP these results are consistent with the fact that both the protonated electron and hydroxyl radical adducts of TMP will covalently bind to the nitroxide function of the probe. Reduction of the PROXYL probe was observed in reactions with the hydroxyl radical adduct of dCMP and with the electron adducts of dAMP, dCMP, and dGMP. Results of the radiolysis of the free PROXYL probe in deaerated dilute solution of DNA suggest that the PROXYL probe protects the DNA from water radical attack as the ratio of DNA bases to PROXYL probe increases above 50:1. Reactions of DNA-bound probes are dependent on the depth of the nitroxide function in relation to the major groove of the DNA helix. Two probes with tether lengths which are less than the depth of the major groove show an expected increase in reactions with DNA base radicals as compared to a probe with a tether that extends beyond the groove. The longer probe is involved largely in reactions with sugar and water radicals along the periphery of the DNA helix. In the presence of oxygen, there is a dramatic decrease in the loss of both the free and DNA-bound probes due to the lack of reaction of these probes with peroxyl radicals formed by the addition of molecular oxygen to DNA radicals.