title: 3-Hydroxy-4-pyridinone derivatives designed for fluorescence studies to determine interaction with amyloid protein as well as cell permeability.
abstract: Finding a cure for Alzheimer's disease is an urgent goal. Multifunctional metal binders are used to elucidate its pathological features and investigated as potential therapeutics. The use of physicochemical and TD-DFT calculations constituted successful strategy in the design of 1-(4-(benzo[d]oxazol-2-yl)phenyl)-3-hydroxy-2-methylpyridin-4(1H)-one (HL21) and 1-(4-(benzo[d]thiazol-2-yl)phenyl)-3-hydroxy-2-methylpyridin-4(1H)-one (HL22). We report the synthesis and full characterization of these compounds, including X-ray crystallography. Using fluorescent signal as the readout, it was determined that HL22 interacts with amyloid-beta protein fibrils, and permeates into bEnd.3 cells used as a mimic of the blood-brain barrier. This provides the first example of direct investigation of our hydroxypyridinone compounds within a biological setting.
authors.affiliation: Medicinal Inorganic Chemistry Group, Department of Chemistry, University of British Columbia, 2036 Main Mall, Vancouver, BC V6T 1Z1, Canada.
authors.forename: Maria A
authors.initials: MA
authors.lastname: Telpoukhovskaia
authors.affiliation: Medicinal Inorganic Chemistry Group, Department of Chemistry, University of British Columbia, 2036 Main Mall, Vancouver, BC V6T 1Z1, Canada.
authors.forename: Jacqueline F
authors.initials: JF
authors.lastname: Cawthray
authors.affiliation: Medicinal Inorganic Chemistry Group, Department of Chemistry, University of British Columbia, 2036 Main Mall, Vancouver, BC V6T 1Z1, Canada.
authors.forename: Cristina
authors.initials: C
authors.lastname: Rodríguez-Rodríguez
authors.affiliation: Medicinal Inorganic Chemistry Group, Department of Chemistry, University of British Columbia, 2036 Main Mall, Vancouver, BC V6T 1Z1, Canada.
authors.forename: Lauren E
authors.initials: LE
authors.lastname: Scott
authors.affiliation: Medicinal Inorganic Chemistry Group, Department of Chemistry, University of British Columbia, 2036 Main Mall, Vancouver, BC V6T 1Z1, Canada.
authors.forename: Brent D G
authors.initials: BD
authors.lastname: Page
authors.affiliation: Medicinal Inorganic Chemistry Group, Department of Chemistry, University of British Columbia, 2036 Main Mall, Vancouver, BC V6T 1Z1, Canada.
authors.forename: Brian O
authors.initials: BO
authors.lastname: Patrick
authors.affiliation: Medicinal Inorganic Chemistry Group, Department of Chemistry, University of British Columbia, 2036 Main Mall, Vancouver, BC V6T 1Z1, Canada. Electronic address: orvig@chem.ubc.ca.
authors.forename: Chris
authors.initials: C
authors.lastname: Orvig
mesh_terms: D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects; D002460:Cell Line / Q000187:drug effects; D060326:Chemistry Techniques, Synthetic; D018360:Crystallography, X-Ray; D005453:Fluorescence; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D008958:Models, Molecular; D015394:Molecular Structure; D010539:Permeability; D011728:Pyridones / Q000737:chemistry* / Q000494:pharmacology
chemical_list: D016229:Amyloid beta-Peptides; D011728:Pyridones
keywords: Amyloid-beta; Fluorescent tracker; Metal chelator; TD-DFT; bEnd.3