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Multifunctional pro-ligands as potential Alzheimer’s disease therapeutics

University of British Columbia

Alzheimer’s disease is the most common form of dementia, affecting more than 24 million individuals worldwide. Although the exact causes of disease development and progression are unknown, the amyloid hypothesis links the observed pathologies of elevated metal ion levels (Cu²⁺, Fe³⁺, Zn²⁺), deposition of amyloid peptide in senile plaques, oxidative stress and neurodegeneration in a cohesive manner. As part of a possible intervention for this process, a series of multifunctional pyridinone pro-ligands were designed and synthesised. 3-Hydroxy-4-pyridinones display a high affinity for metal ions - particularly Fe³⁺ and Cu²⁺ - and are readily functionalised by variation of the N-substituent on the heterocyclic ring. The alpha-hydroxyketone functionality serves not only to bind metal ions, but as an antioxidant via phenolic hydrogen donation; in addition, these activities may be masked by glycosylation at the 3-hydroxy position. Seven pyridinone pro-ligands were synthesised, each containing a pyridinone moiety and a second aromatic ring. Five of these pro-ligands incorporate structural features of amyloid imaging agents: 2-methyl-3-hydroxy-1-(4-dimethylaminophenyl)-4(1H)-pyridinone (Hdapp), 2-methyl-3-hydroxy-1-(4-methylaminophenyl)-4(1H)-pyridinone (Hsapp), 1-(4-aminophenyl)-3-hydroxy-2-methyl-4(1H)-pyridinone (Hzapp), 1-(6-benzothiazolyl)-3-hydroxy-2-methyl-4(1H)-pyridinone (Hbt6p) and 1-(2-benzothiazolyl)-3-hydroxy-2-methyl-4(1H)-pyridinone (Hbt2p). The final two compounds, 3-hydroxy-2-methyl-1-phenyl-4(1H)-pyridinone (Hppp) and 1-benzyl-3-hydroxy-2-methyl-4(1H)-pyridinone (Hnbp), were synthesised and compared to probe the impact of linker length modification between the two aromatic rings. In addition to pro-ligand synthesis, their activities were assessed using a number of in vitro assays. Ability to interfere with metal ion-induced amyloid peptide aggregation in solution, antioxidant activity, cytotoxicity, coordination of Cu²⁺ and binding to amyloid fibrils were all assayed on this series. This was done as a preliminary screen to identify promising lead compounds for further development. The compounds displayed marked ability to resolubilise metal ion-aggregated amyloid-beta, excellent antioxidant activity comparable to that of alpha-tocopherol and acceptable cytotoxicity levels. Furthermore, the ligands coordinate Cu²⁺ in the bis, square planar, tetracoordinate fashion typical of 3-hydroxy-4-pyridinones, and their binding to amyloid-beta fibrils was found to be dependent on ring structure. This work incorporates the first examples of rationally-designed small-molecule Alzheimer’s therapeutics incorporating such multifunctionality, and it is expected that the combination will promote more effective Alzheimer’s intervention than current metal ion-binding therapeutics such as clioquinol and other 8-hydroxyquinoline derivatives in development.

Thesis/Dissertation

application/pdf

2009-07-07

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/10317

Chemistry

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/4.0/