title: In vitro studies of 3-hydroxy-4-pyridinones and their glycosylated derivatives as potential agents for Alzheimer's disease.
abstract: Glycosides of 3-hydroxy-4-pyridinones were synthesized and characterized by mass spectrometry, elemental analysis, (1)H and (13)C NMR spectroscopy, and in one case by X-ray crystallography. The Cu(2+) complex of a novel 3-hydroxy-4-pyridinone was synthesized and characterized by IR and X-ray crystallography, showing the ability of these compounds to chelate potentially toxic metal ions. An MTT cytotoxicity assay of a selected glycosylated compound showed a relatively low toxicity of IC(50) = 570 +/- 90 microM in a human breast cancer cell line. The pyridinone glycosides could be cleaved by a broad specificity beta-glycosidase, Agrobacterium sp.beta-glucosidase, and for one compound k(cat) and K(m) were determined to be 19.8 s(-1) and 1.52 mM, respectively. Trolox Equivalent Antioxidant Capacity (TEAC) values were determined for the free pyridinones, indicating the good antioxidant properties of these compounds. Metal-Abeta(1-40) aggregates with zinc and copper were resolubilized by the non-glycosylated pyridinone ligands.
authors.affiliation: Medicinal Inorganic Chemistry Group, Department of Chemistry, University of British Columbia, 2036 Main Mall, Vancouver, BC, CanadaV6T 1Z1.
authors.forename: David E
authors.initials: DE
authors.lastname: Green
authors.forename: Meryn L
authors.initials: ML
authors.lastname: Bowen
authors.forename: Lauren E
authors.initials: LE
authors.lastname: Scott
authors.forename: Tim
authors.initials: T
authors.lastname: Storr
authors.forename: Michael
authors.initials: M
authors.lastname: Merkel
authors.forename: Karin
authors.initials: K
authors.lastname: Böhmerle
authors.forename: Katherine H
authors.initials: KH
authors.lastname: Thompson
authors.forename: Brian O
authors.initials: BO
authors.lastname: Patrick
authors.forename: Harvey J
authors.initials: HJ
authors.lastname: Schugar
authors.forename: Chris
authors.initials: C
authors.lastname: Orvig
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000975:Antioxidants / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D045744:Cell Line, Tumor; D003300:Copper / Q000737:chemistry; D018360:Crystallography, X-Ray; D006027:Glycosides / Q000138:chemical synthesis / Q000737:chemistry* / Q000633:toxicity; D006801:Humans; D007700:Kinetics; D008968:Molecular Conformation; D011728:Pyridones / Q000737:chemistry*
chemical_list: D016229:Amyloid beta-Peptides; D000975:Antioxidants; D006027:Glycosides; D011728:Pyridones; C020366:3-hydroxy-4-pyridone; D003300:Copper