A Dual-Pronged Approach: A Ruthenium(III) Complex That Modulates Amyloid-beta Aggregation and Disrupts Its Formed Aggregates

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.