In vitro studies of 3-hydroxy-4-pyridinones and their glycosylated derivatives as potential agents for Alzheimer's disease

David E. Green; Meryn L. Bowen; Lauren E. Scott; Tim Storr; Michael Merkel; Karin Böhmerle; Katherine H. Thompson; Brian O. Patrick; Harvey J. Schugar; Chris Orvig

doi:10.1039/B918439B

In vitro studies of 3-hydroxy-4-pyridinones and their glycosylated derivatives as potential agents for Alzheimer's disease†

David E. Green,^a Meryn L. Bowen,^a Lauren E. Scott,^a Tim Storr,^a Michael Merkel,^a Karin Böhmerle,^a Katherine H. Thompson,^a Brian O. Patrick,^a Harvey J. Schugar^b and Chris Orvig*^a

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^a Medicinal Inorganic Chemistry Group, Department of Chemistry, University of British Columbia, 2036 Main Mall, Vancouver, BC, Canada
E-mail: orvig@chem.ubc.ca
Tel: 1 604 822 4449

^b Department of Chemistry and Chemical Biology, Rutgers, The State University of New Jersey, 610 Taylor Rd, Piscataway, New Jersey, USA

Abstract

Glycosides of 3-hydroxy-4-pyridinones were synthesized and characterized by mass spectrometry, elemental analysis, ¹H and ¹³C NMR spectroscopy, and in one case by X-ray crystallography. The Cu²⁺ 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 IC₅₀ = 570 ± 90 μM in a human breast cancer cell line. The pyridinone glycosides could be cleaved by a broad specificity beta-glycosidase, Agrobacterium sp.β-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-Aβ_1-40 aggregates with zinc and copper were resolubilized by the non-glycosylated pyridinone ligands.

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In vitro studies of 3-hydroxy-4-pyridinones and their glycosylated derivatives as potential agents for Alzheimer's disease†

Abstract

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In vitro studies of 3-hydroxy-4-pyridinones and their glycosylated derivatives as potential agents for Alzheimer's disease

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