Alzheimer's Disease (AD) is a devastating neurodegenerative disorder where one of the commonly observed pathological hallmarks is extracellular deposits of the peptide amyloid-β (Aβ).
Alzheimer's disease (AD) is a devastating neurological disorder for which soluble oligomers of the peptide amyloid-β (Aβ) are now recognized as the neurotoxic species. Metal-based therapeutics are uniquely suited to target Aβ, with ruthenium-based (Ru) complexes emerging as propitious candidates. Recently, azole-based Ru(III) complexes were observed to modulate the aggregation of Aβ in solution, where the inclusion of a primary amine proximal to the ligand coordination site improved the activity of the complexes. To advance these structure−activity relationships, a series of oxazole-based Ru complexes were prepared and evaluated for their ability to modulate Aβ aggregation. From these studies, a lead candidate, Oc, emerged that had superior activity relative to its azole predecessors in modulating the aggregation of soluble Aβ and diminishing its cytotoxicity. Further evaluation of Oc demonstrated its ability to disrupt formed Aβ aggregates, resulting in smaller amorphous species. Because altering both sides of the aggregation equilibrium for Aβ has not been previously suggested for metal-based complexes for AD, this work represents an exciting new avenue for improved therapeutic success.
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.
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