tempo and 2-ethyl-2-5-5-trimethyl-3-oxazolidinoxyl

The excessive generation of superoxide radicals O2-. with inadequate available defence provided by the enzyme superoxide dismutase (SOD) may result in the development and exacerbation of many of mankind's common illnesses. The native SOD proves too problematic to be used for the prevention and cure of such diseases. A number of metal-independent synthetic SOD mimics, based on organic nitroxides, have been tried as therapeutic interventions. Among the widely studied mimics, 2-ethyl-2,5,5-trimethyl-3-oxazolidinanyl, 2,2,6,6-tetramethyl-1-piperidimyloxy, nitrosoureas, and triazene derivatives have indicated promising results with possible future applications in chemistry, biology, and medicine.

Topics: Cyclic N-Oxides; Drug Therapy; Humans; Oxazoles; Preventive Medicine; Reactive Oxygen Species; Spin Labels; Structure-Activity Relationship; Superoxide Dismutase; Therapeutics

Inhibition of lipid peroxidation by nitroxide radicals and their corresponding hydroxylamines was investigated. The nitroxides were either oxazolidines or piperidines, differing in substitution of the backbone of the molecule (a five or six-membered ring structure, respectively). Concentration requirements for 50% inhibition of microsomal lipid peroxidation varied from 340 to 6 microM for the nitroxides, and from 120 to 3 microM for the hydroxylamines, correlating with lipophilicity and chemical structure. Intramembrane concentrations required for 50% inhibition was independent of lipophilicity when peroxidation was initiated with ADP-Fe2+ but increased with lipophilicity when peroxidation was initiated with t-butylhydroperoxide. During studies of the kinetics of the inhibition, two modes were seen: a delay or a decreased rate of the process. The former mode was seen with the more lipophilic inhibitors. The mechanism of inhibition was similar for all nitroxides and consisted of the following three major components: blocking of primary initiation, prevention of secondary (peroxide-dependent) initiation, and scavenging of various lipoid radicals in the membrane, the major mode of action of the hydroxylamines. Inhibitory efficiency was interpreted in terms of steric hindrance, diffusibility, regeneration of inhibitor, and ability to interact with hydrophilic sites in a hydrophobic environment.

Topics: Adenosine Diphosphate; Animals; Cyclic N-Oxides; Free Radicals; Kinetics; Lipid Peroxidation; Microsomes, Liver; Molecular Structure; Nitrogen Oxides; Oxazoles; Rats; Rats, Inbred Strains; Spin Labels; Structure-Activity Relationship