Biologically Active Metal-Independent Superoxide Dismutase Mimics

Superoxide dismutase (SOD) is an enzyme that detoxifies superoxide (0₂*⁻), a potentially toxic oxygen-derived species. Attempts to increase intracellular concentrations of SOD by direct application are complicated because SOD, being a relatively large molecule, does not readily cross cell membranes. We have identified a set of stable nitroxides that possess SOD-like activity, have the advantage of being low molecular weight, membrane permeable, and metal independent, and at pH 7.0 have reaction rate constants with 0₂^.- ranging from 1.1 X 10³ to 1.3 X 10⁶ M⁻¹ s⁻¹. These SOD mimics protect mammalian cells from damage induced by hypoxanthine / xanthine oxidase and H₂0₂, although they exhibit no catalase-like activity. In addition, the nitroxide SOD mimics rapidly oxidize DNA-Fe¹¹ and thus may interrupt the Fenton reaction and prevent formation of deleterious OH radicals and/or higher oxidation states of metal ions. Whether by SOD-like activity and/or interception of an electron from redox-active metal ions they protect cells from oxidative stress and may have use in basic and applied biological studies.