STUDIES OF STRUCTURE-ACTIVITY RELATIONSHIP OF NITROXIDE FREE-RADICALSAND THEIR PRECURSORS AS MODIFIERS AGAINST OXIDATIVE DAMAGE

The protective effects of stable nitroxides, as well as their hydroxyl amine and amine precursors, have been tested in Chinese hamster V79 ce lls subjected to H2O2 exposure at fixed concentration or exposure to i onizing radiation. Cytotoxicity was evaluated by monitoring the viabil ity of the cells assessed by the clonogenic assay. The compounds teste d at fixed concentration varied in terms of ring size, oxidation state , and ring substituents. Electrochemical studies were carried out to m easure the redox midpoint potentials. The studies show that in the cas e of protection against H2O2 exposure, the protection was determined b y the ring size, oxidation state, and redox midpoint potentials. In ge neral the protection factors followed the order nitroxides > hydroxyla mines > amines. Both the six-membered ring nitroxides and substituted five-membered ring nitroxides were efficient protectors. For six-membe red ring nitroxides, the compounds exhibiting the lowest midpoint pote ntials exhibited maximal protection. In the case of X-radiation, nitro xides were the most protective though some hydroxylamines were also ef ficient. The amines were in some cases found to sensitize the toxicity of aerobic radiation exposure. The protection observed by the nitroxi des was not dependent on the ring size. However, the ring substituents had significant influence on the protection. Compounds containing a b asic side chain were found to provide enhanced protection. The results in this study suggest that these compounds are novel antioxidants whi ch can provide cytoprotection in mammalian cells against diverse types of oxidative insult and identify structural determinants optimal for protection against individual types of damage.