title: Orally Bioavailable Metal Chelators and Radical Scavengers: Multifunctional Antioxidants for the Coadjutant Treatment of Neurodegenerative Diseases.
abstract: Neurodegenerative diseases are associated with oxidative stress that is induced by the presence of reactive oxygen species and the abnormal cellular accumulation of transition metals. Here, a new series of orally bioavailable multifunctional antioxidants (MFAO-2s) possessing a 2-diacetylamino-5-hydroxypyrimidine moiety is described. These MFAO-2s demonstrate both free radical and metal attenuating properties that are similar to the original published MFAO-1s that are based on 1-N,N'-dimethylsulfamoyl-1-4-(2-pyrimidyl)piperazine. Oral bioavailability studies in C57BL/6 mice demonstrate that the MFAO-2s accumulate in the brain at significantly higher levels than the MFAO-1s while achieving similar neural retina levels. The MFAO-2s protect human neuroblastoma and retinal pigmented epithelial cells against hydroxyl radicals in a dose-dependent manner by maintaining cell viability and intracellular glutathione levels. The MFAO-2s outperform clioquinol, a metal attenuator that has been investigated for the treatment of Alzheimer's disease.
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center , 986025 Nebraska Medical Center, Omaha, Nebraska 68198-6025, United States.
authors.forename: Hiroyoshi
authors.initials: H
authors.lastname: Kawada
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center , 986025 Nebraska Medical Center, Omaha, Nebraska 68198-6025, United States.
authors.forename: Peter F
authors.initials: PF
authors.lastname: Kador
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy; D000818:Animals; D000975:Antioxidants / Q000493:pharmacokinetics* / Q000494:pharmacology*; D001682:Biological Availability; D001921:Brain / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002614:Chelating Agents / Q000493:pharmacokinetics* / Q000494:pharmacology*; D007464:Clioquinol / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004847:Epithelial Cells / Q000378:metabolism; D005260:Female; D016166:Free Radical Scavengers / Q000493:pharmacokinetics* / Q000494:pharmacology*; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D008297:Male; D008670:Metals / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D019636:Neurodegenerative Diseases / Q000188:drug therapy*; D011743:Pyrimidines / Q000737:chemistry / Q000494:pharmacology; D012160:Retina / Q000378:metabolism
chemical_list: D000975:Antioxidants; D002614:Chelating Agents; D016166:Free Radical Scavengers; D008670:Metals; D011743:Pyrimidines; D007464:Clioquinol; D005978:Glutathione