title: In vivo evaluation of novel nitroxyl radicals with reduction stability.
abstract: Nitroxyl radicals (nitroxide) have great potential advantages as spin probes, antioxidants, contrast agents, and radiation-protecting agents. However, they are readily reduced by reductants in cells and lose their paramagnetic nature. Recently, tetraethyl-substituted nitroxyl radicals have been reported to have high stability toward reduction by ascorbic acid (AsA). We report the general considerations of tetraethyl nitroxyl radicals for in vivo application. The reason for the low reactivity to AsA reduction was the positive value of Gibbs energy between the tetraethyl nitroxyl radical and AsA. Further, these compounds had an inhibitory effect on lipid peroxidation despite having AsA resistance. They had low antiproliferative effects in HepG2 cells and HUVECs and did not have a lowering effect on blood pressure in animals. Further, after intravenous injection, the ESR signal intensities of tetraethyl-substituted piperidine nitroxyl radicals were very stable in mice over 20 min. These results suggest that tetraethyl-substituted nitroxyl radicals have stability against bioreduction with reductants such as AsA and confer onto them features as antioxidants and paramagnetic tracers/contrast agents. Hence, they will be useful in identifying the foci of oxidative stress in vivo using redox-based imaging approaches.
authors.affiliation: Department of Bio-functional Science, Faculty of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Kinoshita
authors.forename: Ken-ichi
authors.initials: K
authors.lastname: Yamada
authors.forename: Toshihide
authors.initials: T
authors.lastname: Yamasaki
authors.forename: Fumiya
authors.initials: F
authors.lastname: Mito
authors.forename: Mayumi
authors.initials: M
authors.lastname: Yamato
authors.forename: Nuttavut
authors.initials: N
authors.lastname: Kosem
authors.forename: Hisato
authors.initials: H
authors.lastname: Deguchi
authors.forename: Chisato
authors.initials: C
authors.lastname: Shirahama
authors.forename: Yuko
authors.initials: Y
authors.lastname: Ito
authors.forename: Kana
authors.initials: K
authors.lastname: Kitagawa
authors.forename: Nobuhisa
authors.initials: N
authors.lastname: Okukado
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Sakai
authors.forename: Hideo
authors.initials: H
authors.lastname: Utsumi
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000009:adverse effects / Q000378:metabolism / Q000494:pharmacology; D001205:Ascorbic Acid; D001794:Blood Pressure / Q000187:drug effects; D002478:Cells, Cultured; D003287:Contrast Media / Q000009:adverse effects / Q000378:metabolism / Q000494:pharmacology; D004355:Drug Stability; D004578:Electron Spin Resonance Spectroscopy / Q000379:methods; D056945:Hep G2 Cells; D006801:Humans; D015227:Lipid Peroxidation / Q000187:drug effects; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009589:Nitrogen Oxides / Q000009:adverse effects / Q000378:metabolism* / Q000494:pharmacology*; D010084:Oxidation-Reduction; D051381:Rats; D011918:Rats, Inbred SHR; D017207:Rats, Sprague-Dawley
chemical_list: D000975:Antioxidants; D003287:Contrast Media; D009589:Nitrogen Oxides; C039900:nitroxyl; D001205:Ascorbic Acid