Original ContributionIn vivo evaluation of novel nitroxyl radicals with reduction stability
Section snippets
Chemicals
We purchased 4-oxo-2,2,6,6-tetramethylpiperidine-N-oxyl (oxo-TEMPO), hydroxy-TEMPO, and 3-carbamoyl-2,2,5,5-tetramethylpyrrolidine-N-oxyl (carbamoyl-PROXYL) from Sigma–Aldrich (St. Louis, MO, USA). All other reagents were purchased from Wako Pure Chemical Industries (Osaka, Japan) unless stated otherwise.
Synthesis of 2,2,6,6-tetraethyl-4-piperidone-N-oxyl 5, 6
2,6-Dispiro-4′,4″-dithiopyran-4-piperidone 1 was prepared as previously reported [14]. Compound 1 (10 mmol), ethylene glycol (20 mmol), and p-toluenesulfonic acid monohydrate (20 mmol) were
Synthesis and reactivity of 2,2,6,6-tetraethylpiperidine-N-oxyl 5, 6
To improve the synthetic yield of the tetraethyl-substituted compound, ethylene glycol was used as a protecting agent of the ketone group of compound 1 during the desulfurization reaction of Raney–Ni (Fig. 1). The total reaction yield (73%) from compound 1 to 4 was fivefold higher than that of the previous method (15%) [14]. Compound 6 was obtained using sodium borohydride from compound 5, stoichiometrically. The lipophilicity of compounds 5 and 6 was increased compared with tetramethyl
Discussion
Tetramethylpiperidine (TEMPO)-type nitroxyl radicals such as tempol have been widely used as SOD mimics [4], antioxidants [2], and radiation-protecting agents [22]. However, susceptibility to bioreduction remained an issue limiting their utility in imaging and as radioprotectors. We recently reported that tetraethyl-substituted piperidine nitroxyl radicals were very stable against bioreduction by AsA [14]. This feature opens the possibility for their use in therapeutic and imaging applications.
Acknowledgments
This study was partially supported by Development of Systems and Technology for Advanced Measurement and Analysis of the Japan Science and Technology Agency and a Grant-in-Aid for Young Scientists from the Japan Society for the Promotion of Science.
References (28)
Effects of tempol and redox-cycling nitroxides in models of oxidative stress
Pharmacol. Ther.
(2010)- et al.
In vivo detection of free radicals induced by diethylnitrosamine in rat liver tissue
Free Radic. Biol. Med.
(2006) - et al.
Do nitroxide antioxidants act as scavengers of O2−• or as SOD mimics?
J. Biol. Chem.
(1996) - et al.
Stimulation by nitroxides of catalase-like activity of hemeproteins: kinetics and mechanism
J. Biol. Chem.
(1996) - et al.
Kinetic study on ESR signal decay of nitroxyl radicals, potent redox probes for in vivo ESR spectroscopy, caused by reactive oxygen species
Biochim. Biophys. Acta
(2002) - et al.
Reversible reduction of nitroxides to hydroxylamines: roles for ascorbate and glutathione
Free Radic. Biol. Med.
(2007) - et al.
Effective 2, 6-substitution of piperidine nitroxyl radical by carbonyl compound
Tetrahedron
(2010) - et al.
Lipid peroxidation in liver: hydroxy dimethyl carbazole, a new potent inhibitor
Biochem. Biophys. Res. Commun.
(1980) - et al.
Assay for lipid peroxides in animal tissues by thiobarbituric acid reaction
Anal. Biochem.
(1979) - et al.
Use of nitroxides to protect liposomes against oxidative damage
Methods Enzymol.
(2004)
Antiproliferative effect of the piperidine nitroxide tempol on neoplastic and nonneoplastic mammalian cell lines
Free Radic. Biol. Med.
Cytotoxicity of commonly used nitroxide radical spin probes
Life Sci.
Therapeutic and clinical applications of nitroxide compounds
Antioxid. Redox Signaling
A phase I study of topical Tempol for the prevention of alopecia induced by whole brain radiotherapy
Clin. Cancer Res.
Cited by (43)
A radioiodinated nitroxide probe with improved stability against bioreduction for in vivo detection of lipid radicals
2021, Free Radical Biology and MedicineThe cyclic nitroxide antioxidant 4-methoxy-TEMPO decreases mycobacterial burden in vivo through host and bacterial targets
2019, Free Radical Biology and MedicinePro-fluorescent mitochondria-targeted real-time responsive redox probes synthesised from carboxy isoindoline nitroxides: Sensitive probes of mitochondrial redox status in cells
2018, Free Radical Biology and MedicineCitation Excerpt :These changes decrease the rate of reduction and prolong nitroxide lifetime. Specifically, replacement of the four methyl groups that cradle the nitroxide spin with larger, more electron-rich ethyl groups, extends the nitroxide lifetime both in vitro [15] and in vivo [16]. Building on these ideas, we subsequently developed tetraethylisoindoline nitroxides substituted with carboxy groups [17] and used these to make a fluorescein-based PFN (2b, R2 = –CH2CH3).