Orally Bioavailable Metal Chelators and Radical Scavengers: Multifunctional Antioxidants for the Coadjutant Treatment of Neurodegenerative Diseases
| Autor: | Hiroyoshi Kawada, Peter F. Kador |
|---|---|
| Rok vydání: | 2015 |
| Předmět: |
Male
Cell Survival Radical Biological Availability medicine.disease_cause Antioxidants Retina Mice Alzheimer Disease Neuroblastoma Cell Line Tumor Drug Discovery medicine Moiety Animals Humans Viability assay Chelating Agents chemistry.chemical_classification Reactive oxygen species Dose-Response Relationship Drug Chemistry Clioquinol Brain Epithelial Cells Neurodegenerative Diseases Free Radical Scavengers medicine.disease Glutathione Bioavailability Mice Inbred C57BL Pyrimidines Biochemistry Metals Molecular Medicine Female Oxidative stress medicine.drug |
| Zdroj: | Journal of medicinal chemistry. 58(22) |
| ISSN: | 1520-4804 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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