title: Synthesis, physical-chemical characterisation and biological evaluation of novel 2-amido-3-hydroxypyridin-4(1H)-ones: Iron chelators with the potential for treating Alzheimer's disease.
abstract: A novel class of 2-amido-3-hydroxypyridin-4-one iron chelators is described. These compounds have been designed to behave as suitable molecular probes which will improve our knowledge of the role of iron in neurodegenerative conditions. Neurodegenerative disorders, such as Alzheimer's disease (AD) and Parkinson disease (PD), can be considered as diverse pathological conditions sharing critical metabolic processes such as protein aggregation and oxidative stress. Interestingly, both these metabolic alterations seem to be associated with the involvement of metal ions, including iron. Iron chelation is therefore a potential therapeutic approach. The physico-chemical (pK(a), pFe(3+) and logP) and biological properties (inhibition of iron-containing enzymes) of these chelators have been investigated in order to obtain a suitable profile for the treatment of neurodegenerative conditions. Studies with neuronal cell cultures confirm that the new iron chelators are neuroprotective against β-amyloid-induced toxicity.
authors.affiliation: Division of Pharmaceutical Science, King's College, Franklin-Wilkins Building, Waterloo Campus, Stamford Street, London SE1 9NH, UK.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Gaeta
authors.forename: Francisco
authors.initials: F
authors.lastname: Molina-Holgado
authors.forename: Xiao L
authors.initials: XL
authors.lastname: Kong
authors.forename: Sarah
authors.initials: S
authors.lastname: Salvage
authors.forename: Sarah
authors.initials: S
authors.lastname: Fakih
authors.forename: Paul T
authors.initials: PT
authors.lastname: Francis
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Williams
authors.forename: Robert C
authors.initials: RC
authors.lastname: Hider
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000096:biosynthesis / Q000378:metabolism; D000818:Animals; D016923:Cell Death / Q000187:drug effects; D002478:Cells, Cultured; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D007502:Iron Chelating Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D051379:Mice; D015335:Molecular Probes / Q000032:analysis / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology; D019636:Neurodegenerative Diseases / Q000188:drug therapy / Q000378:metabolism; D018696:Neuroprotective Agents / Q000032:analysis / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*; D018384:Oxidative Stress / Q000187:drug effects; D011753:Pyrones / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D016229:Amyloid beta-Peptides; D007502:Iron Chelating Agents; D015335:Molecular Probes; D018696:Neuroprotective Agents; D011753:Pyrones