title: 3-Hydroxy-4-pyridinone derivatives as metal ion and amyloid binding agents.
abstract: Metal ions have been implicated in several neurodegenerative diseases, including Alzheimer's disease, as their dyshomeostasis may lead to production of reactive oxygen species as well as increased toxicity of amyloid protein aggregates. In this work, we present design and synthesis of three novel multifunctional hydroxypyridinone ligands, HL11, HL12, and HL13, bearing benzothiazole and benzoxazole functionalities. We study the ability of these compounds to bind metal ions Cu(II), Zn(II), and Fe(III), as well as their antioxidant activity and cytotoxicity. Additionally, we determine the pro-ligands' (compounds prior to chelation) propensity to target amyloid protein. Through these studies we determine the effect of combining amyloid- and metal-binding functionalities within the HPO scaffold on different aspects of AD pathology.
authors.affiliation: Medicinal Inorganic Chemistry Group, Department of Chemistry, University of British Columbia, 2036 Main Mall, Vancouver, BC V6T 1Z1, Canada. orvig@chem.ubc.ca.
authors.forename: Maria A
authors.initials: MA
authors.lastname: Telpoukhovskaia
authors.forename: Cristina
authors.initials: C
authors.lastname: Rodríguez-Rodríguez
authors.forename: Jacqueline F
authors.initials: JF
authors.lastname: Cawthray
authors.forename: Lauren E
authors.initials: LE
authors.lastname: Scott
authors.forename: Brent D G
authors.initials: BD
authors.lastname: Page
authors.forename: Jorge
authors.initials: J
authors.lastname: Alí-Torres
authors.forename: Mariona
authors.initials: M
authors.lastname: Sodupe
authors.forename: Gwendolyn A
authors.initials: GA
authors.lastname: Bailey
authors.forename: Brian O
authors.initials: BO
authors.lastname: Patrick
authors.forename: Chris
authors.initials: C
authors.lastname: Orvig
mesh_terms: D000682:Amyloid / Q000378:metabolism* / Q000648:ultrastructure; D016229:Amyloid beta-Peptides / Q000737:chemistry; D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D002460:Cell Line; D002839:Chromans / Q000378:metabolism; D007477:Ions; D008024:Ligands; D008670:Metals / Q000378:metabolism*; D051379:Mice; D008958:Models, Molecular; D009391:Nephelometry and Turbidimetry; D020836:Protein Structure, Quaternary; D011728:Pyridones / Q000378:metabolism*; D011789:Quantum Theory; D012996:Solutions; D013057:Spectrum Analysis; D055672:Static Electricity
chemical_list: D000682:Amyloid; D016229:Amyloid beta-Peptides; D000975:Antioxidants; D002839:Chromans; D007477:Ions; D008024:Ligands; D008670:Metals; D011728:Pyridones; D012996:Solutions; C010643:6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid