Studies of Structure−Activity Relationship of Nitroxide Free Radicals and Their Precursors as Modifiers Against Oxidative Damage

Abstract

The protective effects of stable nitroxides, as well as their hydroxylamine and amine precursors, have been tested in Chinese hamster V79 cells subjected to H2O2 exposure at fixed concentration or exposure to ionizing radiation. Cytotoxicity was evaluated by monitoring the viability of the cells assessed by the clonogenic assay. The compounds tested at fixed concentration varied in terms of ring size, oxidation state, and ring substituents. Electrochemical studies were carried out to measure the redox midpoint potentials. The studies show that in the case of protection against H2O2 exposure, the protection was determined by the ring size, oxidation state, and redox midpoint potentials. In general the protection factors followed the order nitroxides > hydroxylamines > amines. Both the six-membered ring nitroxides and substituted five-membered ring nitroxides were efficient protectors. For six-membered ring nitroxides, the compounds exhibiting the lowest midpoint potentials exhibited maximal protection. In the case of X-radiation, nitroxides were the most protective though some hydroxylamines were also efficient. The amines were in some cases found to sensitize the toxicity of aerobic radiation exposure. The protection observed by the nitroxides was not dependent on the ring size. However, the ring substituents had significant influence on the protection. Compounds containing a basic side chain were found to provide enhanced protection. The results in this study suggest that these compounds are novel antioxidants which can provide cytoprotection in mammalian cells against diverse types of oxidative insult and identify structural determinants optimal for protection against individual types of damage.

The chemistry and biology of nitroxide compounds

“…Nitroxides of three different ring types were studied, namely the five-membered saturated pyrrolidine ring, the five-membered unsaturated pyrroline ring, and the six-membered saturated ring piperidine. The ring oxidation states tested were the nitroxide radical form (X = -O • ) and its corresponding hydroxylamine (X = -OH) [21]. Several observations can be made from this study.…”

Assessment of tumor oxygenation by electron paramagnetic resonance: principles and applications

“…However, little or no toxic effect has been recorded so far using these compounds. [239][240][241][242][243] For paramagnetic particulate materials, initial clinical 68 for details studies have already begun using India ink, which has been used in humans without toxicity for several centuries. 181,182 The first clinical trial, which was approved and begun at Dartmouth Medical School, will use India ink as an oxygen sensor.…”

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

“…1). The hydroxylamines can function as typical reducing agents, like vitamin C or E, to scavenge oxidants (Krishna et al, 1998). Therefore, TEMPO has been considered an antioxidant because it can mimic superoxide dismutase, inhibit hydroxyl radical generation, act as a hydrogen donor antioxidant, neutralize carbon-centered free radicals, and mimic the enzymatic activity of catalase (Castagna et al, 2009).…”