SOD activity of carboxyfullerenes predicts their neuroprotective efficacy: a structure-activity study.
Superoxide radical anion is a biologically important oxidant that has been linked to tissue injury and inflammation in several diseases. Here we carried out a structure-activity study on six different carboxyfullerene superoxide dismutase (SOD) mimetics with distinct electronic and biophysical characteristics. Neurotoxicity via N-methyl-D-aspartate receptors, which involves intracellular superoxide, was used as a model to evaluate structure-activity relationships between reactivity toward superoxide and neuronal rescue by these drugs. A significant correlation between neuroprotection by carboxyfullerenes and their ki toward superoxide radical was observed. Computer-assisted molecular modeling demonstrated that the reactivity toward superoxide is sensitive to changes in dipole moment, which are dictated not only by the number of carboxyl groups but also by their distribution on the fullerene ball. These results indicate that the SOD activity of these cell-permeable compounds predicts neuroprotection, and establishes a structure-activity relationship to aid in future studies on the biology of superoxide across disciplines.
Ali
Sameh Saad
SS
Department of Medicine, University of California, San Diego, California, USA. ssali@ucsd.edu
Hardt
Joshua I
JI
Dugan
Laura L
LL
D000818:Animals; D040761:Biomimetic Materials / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D016166:Free Radical Scavengers / Q000378:metabolism; D037741:Fullerenes / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D051379:Mice; D008958:Models, Molecular; D015394:Molecular Structure; D016202:N-Methylaspartate / Q000494:pharmacology; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D018696:Neuroprotective Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D011485:Protein Binding; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D013329:Structure-Activity Relationship; D013482:Superoxide Dismutase / Q000378:metabolism*; D013481:Superoxides / Q000378:metabolism
D016166:Free Radical Scavengers; D037741:Fullerenes; D018696:Neuroprotective Agents; D016194:Receptors, N-Methyl-D-Aspartate; D013481:Superoxides; D016202:N-Methylaspartate; D013482:Superoxide Dismutase