Journal
INORGANIC CHEMISTRY
Volume 61, Issue 6, Pages 2733-2744Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.inorgchem.1c01651
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Funding
- National Science Foundation [CHE-103689, CHE-0722385, CHE-1807126]
- College of Arts and Sciences
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This study found that oxazole-based ruthenium complexes can modulate the aggregation of Aβ in solution, with a lead candidate Oc showing superior activity compared to its azole predecessors, potentially improving the success of therapeutic interventions for Alzheimer's disease.
Alzheimer's disease (AD) is a devastating neurological disorder for which soluble oligomers of the peptide amyloid-beta (A beta) are now recognized as the neurotoxic species. Metal-based therapeutics are uniquely suited to target A beta, with ruthenium-based (Ru) complexes emerging as propitious candidates. Recently, azole-based Ru(III) complexes were observed to modulate the aggregation of A beta 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 A beta aggregation. From these studies, a lead candidate, Oc, emerged that had superior activity relative to its azole predecessors in modulating the aggregation of soluble A beta and diminishing its cytotoxicity. Further evaluation of Oc demonstrated its ability to disrupt formed A beta aggregates, resulting in smaller amorphous species. Because altering both sides of the aggregation equilibrium for A beta has not been previously suggested for metal-based complexes for AD, this work represents an exciting new avenue for improved therapeutic success.
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