Biologically active metal-independent superoxide dismutase mimics.
Superoxide dismutase (SOD) is an enzyme that detoxifies superoxide (O2.-), 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 O2.- ranging from 1.1 x 10(3) to 1.3 x 10(6) M-1 s-1. These SOD mimics protect mammalian cells from damage induced by hypoxanthine/xanthine oxidase and H2O2, although they exhibit no catalase-like activity. In addition, the nitroxide SOD mimics rapidly oxidize DNA-FeII 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.
Mitchell
J B
JB
Radiation Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892.
Samuni
A
A
Krishna
M C
MC
DeGraff
W G
WG
Ahn
M S
MS
Samuni
U
U
Russo
A
A
D000818:Animals; D002478:Cells, Cultured; D055598:Chemical Phenomena; D002621:Chemistry; D006224:Cricetinae; D003574:Cytochrome c Group / Q000378:metabolism; D004247:DNA / Q000378:metabolism; D004578:Electron Spin Resonance Spectroscopy; D005296:Ferrous Compounds / Q000378:metabolism; D009589:Nitrogen Oxides / Q000378:metabolism; D010080:Oxazoles; D010084:Oxidation-Reduction; D013482:Superoxide Dismutase / Q000235:genetics
D003574:Cytochrome c Group; D005296:Ferrous Compounds; D009589:Nitrogen Oxides; D010080:Oxazoles; C064210:oxazolidine; D004247:DNA; D013482:Superoxide Dismutase