The chemistry and biology of nitroxide compounds

Abstract

Cyclic nitroxides are a diverse range of stable free radicals that have unique antioxidant properties. Because of their ability to interact with free radicals, they have been used for many years as biophysical tools. During the past 15-20 years, however, many interesting biochemical interactions have been discovered and harnessed for therapeutic applications. Biologically relevant effects of nitroxides have been described including their ability to degrade superoxide and peroxide, inhibit Fenton reactions and undergo radical-radical recombination. Cellular studies defined the activity of nitroxides in vitro. By modifying oxidative stress and altering the redox status of tissues, nitroxides have been found to interact with and alter many metabolic processes. These interactions can be exploited for therapeutic and research use including protection against ionizing radiation, as probes in functional magnetic resonance imaging, cancer prevention and treatment, control of hypertension and weight, and protection from damage resulting from ischemia/reperfusion injury. While much remains to be done, many applications have been well studied and some are presently being tested in clinical trials. The therapeutic and research uses of nitroxide compounds are reviewed here with a focus on the progress from initial development to modern trials.

Superoxide Dismutase Mimics: Chemistry, Pharmacology, and Therapeutic Potential

“…Tempol was washed off after the completion of the daily radiation fraction. Tempol remained on the scalp for *30-45 min each day and was well tolerated (296). Tempol also decreased radiationinduced salivary hypofunction with C3H mice (297).…”

“…A detailed review of the protective effects of nitroxides was published by Soule et al (296,297) and is briefly summarized here. Nitroxides were shown to be radioprotective when given IP to mice before radiation.…”

“…The radiation LD 50=30 (radiation that caused 50% lethality in C3H mice in 30 days) was 7.84 Gy without and 9.97 with Tempol in a study in which mice were exposed to whole-body radiation. Tempol was injected at 275 mg=kg, 5-10 min before radiation exposure (147,296). In vitro, reduced Tempol (hydroxylamine) was not efficient in protecting Chinese hamster cells against radiation, whereas Tempol was most effective at 50 mM levels (297).…”

Nitroxide TEMPO: A genotoxic and oxidative stress inducer in cultured cells

“…Nitroxides have a reducible nitroxide group ( · N-O) as part of a five-or six-carbon ring (Soule et al, 2007;Wilcox and Pearlman, 2008). Piperidine nitroxides are a diverse group of stable free radicals classically used as spin probes in electron paramagnetic resonance spectroscopy (Matsumoto et al, 2004), as paramagnetic contrast agents in nuclear magnetic resonance imaging (Bennett et al, 1987), and as oxygen-sensitive probes in biological systems (Strzalka et al, 1990).…”

Monitoring redox-sensitive paramagnetic contrast agent by EPRI, OMRI and MRI

“…These EPRI measurements are based on the fact that the paramagnetic nitroxides are reduced to the corresponding diamagnetic one-electron reduction product (Fig. 1A), hydroxylamine in cellular incubations as well as in vivo [5][6][7][8]. It was postulated that nitroxides can accept cellular reducing equivalents, especially from the mitochondrial electron transport chain that would have otherwise gone to the reduction of molecular oxygen [9].…”