Novel potential neuroprotective agents with both iron chelating and amino acid-based derivatives targeting central nervous system neurons.
Antioxidants and iron chelating molecules are known as neuroprotective agents in animal models of neurodegenerative disorders such as Alzheimer's disease (AD) and Parkinson's disease (PD). In this study, we designed and synthesized a novel bifunctional molecule (M10) with radical scavenging and iron chelating ability on an amino acid carrier likely to be a substrate for system L, thus targeting the compound to the central nervous system (CNS). M10 had a moderate iron affinity in HEPES buffer (pH 7.4) with logK(3)=12.25+/-0.55 but exhibited highly inhibitory action against iron-induced lipid peroxidation, with an IC(50) value (12microM) comparable to that of desferal (DFO). EPR studies indicated that M10 was a highly potent *OH scavenger with an IC(50) of about 0.3 molar ratio of M10 to H(2)O(2). In PC12 cell culture, M10 was at least as potent as the anti-Parkinson drug rasagiline in protecting against cell death induced by serum-deprivation and by 6-hydroxydopamine (6-OHDA). These results suggest that M10 deserves further investigation as a potential agent for the treatment of neurodegenerative disorders such as AD and PD.
Zheng
Hailin
H
Department of Organic Chemistry, The Weizmann Institute of Science, Herzl St., Rehovot 76100, Israel.
Youdim
Moussa B H
MB
Weiner
Lev M
LM
Fridkin
Mati
M
D000409:Alanine / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology; D000596:Amino Acids / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D016895:Culture Media, Serum-Free / Q000494:pharmacology; D004353:Drug Evaluation, Preclinical; D016166:Free Radical Scavengers / Q000494:pharmacology; D006892:Hydroxydopamines / Q000494:pharmacology; D017665:Hydroxyl Radical / Q000378:metabolism; D006912:Hydroxyquinolines / Q000737:chemistry / Q000494:pharmacology; D007501:Iron / Q000378:metabolism*; D007502:Iron Chelating Agents / Q000378:metabolism / Q000494:pharmacology*; D015227:Lipid Peroxidation / Q000187:drug effects; D015394:Molecular Structure; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D018696:Neuroprotective Agents / Q000737:chemistry* / Q000494:pharmacology*; D016716:PC12 Cells; D051381:Rats
C506272:3-(8-hydroxyquinolin-5-yl)alanine; D000596:Amino Acids; D016895:Culture Media, Serum-Free; D016166:Free Radical Scavengers; D006892:Hydroxydopamines; D006912:Hydroxyquinolines; D007502:Iron Chelating Agents; D018696:Neuroprotective Agents; D017665:Hydroxyl Radical; D007501:Iron; D000409:Alanine