In vivo evaluation of novel nitroxyl radicals with reduction stability

Kinoshita, Yuichi; Yamada, Ken Ichi; Yamasaki, Toshihide; Mito, Fumiya; Yamato, Masayuki; Kosem, Nuttavut; Deguchi, Hisato; Shirahama, Chisato; Ito, Yuko; Kitagawa, Kota; Okukado, Nobuhisa; Saito, Kiyoshi; Utsumi, Hideo

doi:10.1016/j.freeradbiomed.2010.08.027

Cited by 49 publications

(38 citation statements)

References 26 publications

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“…Sterically shielded nitroxides 7, 10 and 11 were synthesized according to the method established by Yamada's group [4][5][6][7] and Rajca's group. [9][10][11] Since there were some low-yield reaction steps in the synthesis of the sterically shielded nitroxides (7, 10, 11), the reaction conditions were partially improved and synthesis was achieved.…”

Section: Resultsmentioning

confidence: 99%

“…They had different reduction rates for reductants such as ascorbic acid (AsA), and these were applied as an invivo probe. [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17] The rate constant of reduction of a nitroxide probe in vitro is expected to be a guideline of its half-life in vivo. [9][10][11] The rate constants of them are greatly different and could not measure under the same conditions.…”

mentioning

confidence: 99%

“…The balance between their sensitivity for reductants and half-life is important for use of nitroxide as an in-vivo probe. TEMPO radical is highly sensitive for reductants and a good detection reagent for AsA, 5,11) but, its half-life as an in-vivo probe was too short and unusable. 14) It has been shown that ibuprofen-PROXYL passed through the blood-brain barrier (BBB) in mice and was indicated the anti-inflammatory action in inflamed mice brains.…”

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confidence: 99%

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Synthesis and Reduction Kinetics of Five Ibuprofen–Nitroxides for Ascorbic Acid and Methyl Radicals

et al. 2016

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).Key words Ibuprofen-nitroxide; reduction kinetics; ascorbic acid; methyl radical; Fenton reaction; electron paramagnetic resonance intensityThe representative nitroxide radicals, a six-memberedring nitroxide, tetramethylpiperidine-1-oxyl (TEMPO), and a five-membered-ring nitroxide, tetramethylpyrrolidine-1-oxyl (PROXYL), have been used as in-vivo probes. Recently, various nitroxides in which the tetramethyl groups around the nitroxyl group were replaced by bulkier groups have been synthesized. They had different reduction rates for reductants such as ascorbic acid (AsA), and these were applied as an invivo probe. [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17] The rate constant of reduction of a nitroxide probe in vitro is expected to be a guideline of its half-life in vivo.9-11) The rate constants of them are greatly different and could not measure under the same conditions. 9,10,17) For the nitroxides resistant to AsA, we planned to examine the measurement of their rate constants using methyl radicals formed by Fenton reaction. The balance between their sensitivity for reductants and half-life is important for use of nitroxide as an in-vivo probe. TEMPO radical is highly sensitive for reductants and a good detection reagent for AsA, 5,11) but, its half-life as an in-vivo probe was too short and unusable. 14) It has been shown that ibuprofen-PROXYL passed through the blood-brain barrier (BBB) in mice and was indicated the anti-inflammatory action in inflamed mice brains. Real-time changes in the redox status of mice brains were successfully visualized by magnetic resonance imaging (MRI) and electron paramagnetic resonance (EPR) imaging. Both shows a functionality as a theranostic compound.18) However, for exploring the redox status of brain, nitroxides with different reduction rate for reductants such as reactive oxygen species (ROS) or vitamin C or E are required. Five nitroxides with different reduction activities and their condensates with ibuprofen were synthesized (Fig. 1). The reduction reactivity of the five ibuprofen-nitroxides were measured by addition of AsA, and for the reduction-resistant nitroxides by the addition of the methyl radicals produced by the Fenton reaction. The reduction rate constants of the five ibuprofen-nitroxides for AsA or methyl radicals were determined and compared with the suitable time-dependent reduction-decay curve. Results and DiscussionSynthesis Six nitroxides (6-11) were synthesized by the synthetic methods shown in Chart S1. Sterically shielded nitroxides 7, 10 and 11 were synthesized according to the method established by Yamada's group 4-7) and Rajca's group. [9][10][11] Since there were some low-yield reaction steps in the synthesis of the sterically shielded nitroxides (7, 10, 11), the reaction conditions were partially improved and synthesis was achieved.Nitroxides with tetramethyl groups 6, 8 and 9 were synthesized by conventional methods. [19][20][21]

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Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

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confidence: 99%

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Synthesis and Reduction Kinetics of Five Ibuprofen–Nitroxides for Ascorbic Acid and Methyl Radicals

et al. 2016

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“…Benial et al reported that the permeability studies of redox sensitive nitroxyl spin probes through lipid membranes using an L-band ESR spectrometer [22]. Kinoshita et al also reported the synthesis of tetraethyl-substitued nitroxyl radicals, which exhibit remarkable resistivity towards ascorbic acid reduction during invivo testing [23].…”

Section: Introductionmentioning

confidence: 99%

Comparative Study of the Reduction Process of Different Ring Structured Nitroxyl Spin Probes: An Electron Spin Resonance Study

Meenakumari¹

2016

EJB

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Electron spin resonance spectroscopy (ESR) studies on the reduction process of nitroxyl spin probes were carried out for 1mM concentration of 14 N-labeled pyrrolidine nitroxyl spin probes, 3-carbamoyl-2,2,5,5-tetramethyl-pyrrolidine-1-oxyl (carbamoyl-PROXYL) and 3-carboxy-2,2,5,5-tetramethyl-pyrrolidine -1-oxyl (carboxy-PROXYL), 14 N-labeled piperidine nitroxyl spin probes, 4-methoxy-2,2,6,6-tetramethyl-piperidine-1-oxyl (methoxy-TEMPO) and 4-acetamido-2,2,6,6-tetramethyl-piperidine-1-oxyl (acetamido-TEMPO) in 1 mM concentration of ascorbic acid as a function of time. The half-life time and decay rate were estimated. The piperidine nitroxyl spin probes show a short half-life time compared with that of pyrrolidine nitroxyl spin probes. This result indicates that the higher stability of pyrrolidine nitroxyl spin probes. The ESR was also recorded for 1mM concentration of pyrrolidine nitroxyl spin probes and piperidine nitroxyl spin probes in pure water using X-band ESR spectrometer. The ESR parameters such as line width, hyperfine coupling constant, g-factor, signal intensity ratio and rotational correlation time were determined. These results indicate that the pyrrolidine nitroxyl spin probes have narrow line width and fast tumbling compared with the piperidine nitroxyl spin probes. Therefore, this study reveals that the pyrrolidine nitroxyl spin probes can act as good redox sensitive spin probes for free radical imaging.

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“…Utsumi et al reported that the Dynamic nuclear polarization (DNP) properties of nitroxyl radicals used in Overhauser-enhanced magnetic resonance imaging for simultaneous molecular imaging of redox reactions [24]. Recently, the stable nitroxyl radicals have been used as redox sensitive probe for in vivo ESR and OMR imaging techniques [25][26][27][28][29][30][31]. This proposed work determines the half life time and the signal decay rate for the piperidine nitroxyl radicals.…”

Section: Introductionmentioning

confidence: 99%

Electron Spin Resonance Spectroscopy Studies on Reduction Process of Nitroxyl Radicals used in Molecular Imaging

Dhas¹,

Jawahar²,

Benial³

2014

EJB

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Abstract:Electron spin resonance (ESR) spectroscopy studies on the reduction process of nitroxyl radicals were carried out for 1mM concentration of 14 N-labeled nitroxyl radicals in 1 mM concentration of ascorbic acid as a function of time. The half life time and decay rate were estimated for 1mM concentration of 14 N labeled nitroxyl radicals in 1 mM concentration of ascorbic acid. From the results, the increase in half life time and decrease in decay rate were calculated for TEMPONE compared with TEMPO and TEMPOL radicals, which indicates the higher stability of TEMPONE radical. The observed radical scavenging activity is also higher for TEMPONE radical. The ESR spectrum was also recorded for 1mM concentration of 14 N-labeled nitroxyl radicals in pure water and the ESR parameters, line width, hyperfine coupling constant, g-factor, signal intensity ratio and rotational correlation time were obtained. These results indicate that the TEMPONE radical has narrowest line width and fast tumbling motion compared with TEMPO and TEMPOL. Therefore, this study reveals that the TEMPONE radical can act as a good redox sensitive spin probe for molecular imaging.

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In vivo evaluation of novel nitroxyl radicals with reduction stability

Cited by 49 publications

References 26 publications

Synthesis and Reduction Kinetics of Five Ibuprofen–Nitroxides for Ascorbic Acid and Methyl Radicals

Synthesis and Reduction Kinetics of Five Ibuprofen–Nitroxides for Ascorbic Acid and Methyl Radicals

Comparative Study of the Reduction Process of Different Ring Structured Nitroxyl Spin Probes: An Electron Spin Resonance Study

Electron Spin Resonance Spectroscopy Studies on Reduction Process of Nitroxyl Radicals used in Molecular Imaging

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