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UBC Theses and Dissertations

Novel multifunctional ligands and their application in Alzheimer’s disease Telpoukhovskaia, Maria A.


Alzheimer’s disease (AD) is a fatal, neurodegenerative disorder that is the most common cause of dementia currently affecting over 35 million people. Metal ions Cu(II), Zn(II), and Fe(III) have a dual deleterious role in Alzheimer’s disease through acceleration of aggregation that leads to increased toxicity of the amyloid protein, and participation in catalytic cycles generating reactive species. The therapeutic effect of metal chelating agents is currently explored in clinical studies, as there are currently no drugs for this disease. This thesis investigates the 3-hydroxy-4-pyridinone family of chelating ligands, with attention given to its multifunctional activities. The main goal is to demonstrate that metal and amyloid-binding functionalities are compatible within this scaffold, while other functionalities are retained. Novel chelating agents 1-(benzo[d]oxazol-2-ylmethyl)-3-hydroxy-2-methylpyridin-4(1H)-one (Hmbo2p), 1-(benzo[d]thiazol-2-ylmethyl)-3-hydroxy-2-methylpyridin-4(1H)-one (Hmbt2p), 1-(2-aminobenzo[d]thiazol-6-yl)-3-hydroxy-2-methylpyridin-4(1H)-one (Habt6p), 1-(4-(benzo[d]oxazol-2-yl)phenyl)-3-hydroxy-2-methylpyridin-4(1H)-one (Hpbo2p), and 1-(4-(benzo[d]thiazol-2-yl)phenyl)-3-hydroxy-2-methylpyridin-4(1H)-one (Hpbt2p) were designed, synthesised, and structural characterised. The metal binding of Hmbo2p to Cu(II), Zn(II), and Fe(III) was confirmed with titration studies, while the solid state structures of Hmbt2p were characterised using X-ray crystallography. Amyloid binding functionalities of Hmbo2p were confirmed with microscopy, fluorescence, and binding studies. Moreover, the radical quenching ability of Hmbo2p was established in the absence and presence of Cu(II) by absorbance and fluorescence studies. As well, compounds Hmbo2p, Hmbt2p, and Habt6p were found to be relatively toxic in a mouse endothelial neuronal cell line, while Hpbt2p was visualised to permeate into the cell line. Finally, by installing a carbamoyl functionality, novel compounds 2-methyl-4-oxo-1-phenyl-1,4-dihydropyridin-3-yl dimethylcarbamate (Cppp), 4-(3-hydroxy-2-methyl-4-oxopyridin-1(4H)-yl)phenyl dimethylcarbamate (Chpp), and 4-(((2-methyl-4-oxo-1-phenyl-1,4-dihydropyridin-3-yl)oxy)methyl)phenyl dimethylcarbamate (Cbppp) were synthesised for the purpose of adding an acetylcholinesterase (AChE) inhibitory functionality. The metal chelation site was masked on Cppp and Cbppp; all three inhibited eelAChE reversibly in vitro. The work presented herein demonstrates for the first time that incorporation of benzoxazole group into the hydroxypyridinone scaffold imbues it with amyloid-binding functionality while retaining the metal chelating ability. This insertion and concomitant increase of lipophilicity leads to morphological changes of amyloid protein upon incubation, and potentially results in increased toxicity and cell permeability. Finally, masking the hydroxyl group with a carbamate functionality on the scaffold leads to generation of reversible enzyme inhibitors.

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