Multifunctional antioxidants for the treatment of age-related diseases.
Analogues of N,N-dimethyl-4-(pyrimidin-2-yl)piperazine-1-sulfonamide possessing a free radical scavenger group (FRS), chelating groups (CHL), or both (FRS + CHL) have been synthesized. Electrospray ionization mass spectrometry studies indicate that select members of this series bind ions in the relative order of Cu(1+) = Cu(2+) > Fe(2+) = Fe(3+) > Zn(2+) with no binding of Ca(2+) or Mg(2+) observed. In vitro evaluation of these compounds in human lens epithelial, human retinal pigmented epithelial, and human hippocampal astrocyte cell lines indicates that all analogues possessing the FRS group as well as the water-soluble vitamin E analogue 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid protect these cells against decreased cell viability and glutathione levels induced by hydrogen peroxide. In addition, those compounds possessing CHL groups also protected these cells against hydroxyl radicals generated by the Fenton reaction. These compounds are good candidates for the preventive treatment of cataract, age-related macular degeneration (AMD), and Alzheimer's dementia (AD).
Jin
Hongxia
H
College of Pharmacy, University of Nebraska Medical Center, Omaha, Nebraska 68198, USA.
Randazzo
James
J
Zhang
Peng
P
Kador
Peter F
PF
D000375:Aging / Q000187:drug effects* / Q000473:pathology; D000975:Antioxidants / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001253:Astrocytes / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002614:Chelating Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D016166:Free Radical Scavengers / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D005978:Glutathione / Q000378:metabolism; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D009682:Magnetic Resonance Spectroscopy; D016877:Oxidants / Q000494:pharmacology; D018384:Oxidative Stress; D010857:Pigment Epithelium of Eye / Q000166:cytology / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism; D021241:Spectrometry, Mass, Electrospray Ionization; D013449:Sulfonamides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
D000975:Antioxidants; D002614:Chelating Agents; D016166:Free Radical Scavengers; D016877:Oxidants; D017382:Reactive Oxygen Species; D013449:Sulfonamides; D006861:Hydrogen Peroxide; D005978:Glutathione