Importance of Hydrogen Bonding: Structure–Activity Relationships of Ruthenium(III) Complexes with Pyridine-Based Ligands for Alzheimer’s Disease Therapy
Brendan J. Wall, Mark F. Will, Gideon K. Yawson, Paige J. Bothwell, David C. Platt, C. Fiore Apuzzo, Marjorie A. Jones, Gregory M. Ferrence, Michael I. Webb
Abstract
Alzheimer’s disease (AD) is the most common form of dementia, where one of the pathological hallmarks of AD is extracellular protein deposits, the primary component of which is the peptide amyloid-β (Aβ). Recently, the soluble form of Aβ has been recognized as the primary neurotoxic species, making it an important target for therapeutic development. Metal-based drugs are promising candidates to target Aβ, as the interactions with the peptide can be tuned by ligand design. In the current study, 11 ruthenium complexes containing pyridine-based ligands were prepared, where the functional groups at the para position on the coordinated pyridine ligand were varied to determine structure–activity relationships. Overall, the complexes with terminal primary amines had the greatest impact on modulating the aggregation of Aβ and diminishing its cytotoxicity. These results identify the importance of specific intermolecular interactions and are critical in the advancement of metal-based drugs for AD therapy.