Orally Bioavailable Metal Chelators and Radical Scavengers: Multifunctional Antioxidants for the Coadjutant Treatment of Neurodegenerative Diseases

Hiroyoshi Kawada, Peter F Kador

Research output: Contribution to journalArticle

8 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)8796-8805
Number of pages10
JournalJournal of Medicinal Chemistry
Volume58
Issue number22
DOIs
StatePublished - Nov 25 2015

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Chelating Agents
Neurodegenerative Diseases
Antioxidants
Metals
Clioquinol
Retinoblastoma
Inbred C57BL Mouse
Hydroxyl Radical
Biological Availability
Free Radicals
Glutathione
Retina
Reactive Oxygen Species
Cell Survival
Alzheimer Disease
Oxidative Stress
Epithelial Cells
Brain

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

Cite this

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