Novel multifunctional neuroprotective iron chelator-monoamine oxidase inhibitor drugs for neurodegenerative diseases: in vitro studies on antioxidant activity, prevention of lipid peroxide formation and monoamine oxidase inhibition.
Iron-dependent oxidative stress, elevated levels of iron and of monoamine oxidase (MAO)-B activity, and depletion of antioxidants in the brain may be major pathogenic factors in Parkinson's disease, Alzheimer's disease and related neurodegenerative diseases. Accordingly, iron chelators, antioxidants and MAO-B inhibitors have shown efficacy in a variety of cellular and animal models of CNS injury. In searching for novel antioxidant iron chelators with potential MAO-B inhibitory activity, a series of new iron chelators has been designed, synthesized and investigated. In this study, the novel chelators were further examined for their activity as antioxidants, MAO-B inhibitors and neuroprotective agents in vitro. Three of the selected chelators (M30, HLA20 and M32) were the most effective in inhibiting iron-dependent lipid peroxidation in rat brain homogenates with IC50 values (12-16 microM), which is comparable with that of desferal, a prototype iron chelator that is not has orally active. Their antioxidant activities were further confirmed using electron paramagnetic resonance spectroscopy. In PC12 cell culture, the three novel chelators at 0.1 microM were able to attenuate cell death induced by serum deprivation and by 6-hydroxydopamine. M30 possessing propargyl, the MAO inhibitory moiety of the anti-Parkinson drug rasagiline, displayed greater neuroprotective potency than that of rasagiline. In addition, in vitro, M30 was a highly potent non-selective MAO-A and MAO-B inhibitor (IC50 < 0.1 microM). However, HLA20 was more selective for MAO-B but had poor MAO inhibition, with an IC50 value of 64.2 microM. The data suggest that M30 and HLA20 might serve as leads in developing drugs with multifunctional activities for the treatment of various neurodegenerative disorders.
Zheng
Hailin
H
Department of Organic Chemistry and Neurobiology, The Weizmann Institute of Science, Rehovot, Israel.
Gal
Shunit
S
Weiner
Lev M
LM
Bar-Am
Orit
O
Warshawsky
Abraham
A
Fridkin
Mati
M
Youdim
Moussa B H
MB
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects; D016895:Culture Media, Serum-Free / Q000494:pharmacology; D003545:Cysteine / Q000031:analogs & derivatives / Q000494:pharmacology; D015198:Designer Drugs / Q000494:pharmacology / Q000627:therapeutic use; D017665:Hydroxyl Radical / Q000378:metabolism; D006912:Hydroxyquinolines / Q000494:pharmacology; D007502:Iron Chelating Agents / Q000494:pharmacology* / Q000627:therapeutic use; D015227:Lipid Peroxidation / Q000187:drug effects*; D008996:Monoamine Oxidase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D019636:Neurodegenerative Diseases / Q000188:drug therapy; D018696:Neuroprotective Agents / Q000494:pharmacology* / Q000627:therapeutic use; D016627:Oxidopamine / Q000506:poisoning; D016716:PC12 Cells; D010879:Piperazines / Q000494:pharmacology; D051381:Rats
C517687:5-(N-methyl-N-propargylaminomethyl)-8-hydroxyquinoline; D000975:Antioxidants; D016895:Culture Media, Serum-Free; D015198:Designer Drugs; D006912:Hydroxyquinolines; D007502:Iron Chelating Agents; C505061:M32 compound; D008996:Monoamine Oxidase Inhibitors; D018696:Neuroprotective Agents; D010879:Piperazines; C505060:5-((4-prop-2-ynylpiperazin-1-yl)methyl)quinolin-8-ol; D017665:Hydroxyl Radical; D016627:Oxidopamine; D003545:Cysteine