Finding the best location: Improving the anti-amyloid ability of ruthenium(III) complexes with pyridine ligands

Abstract

Alzheimer's disease (AD) is a devastating neurological disorder where one of the primary pathological hallmarks are aggregate deposits of the peptide amyloid-beta (Aβ). Although the Food and Drug Administration (FDA) has recently approved therapeutics that specifically target Aβ, resulting in the removal of these deposits, the associated costs of such treatments create a need for effective, yet cheaper, alternatives. Metal-based compounds are propitious therapeutic candidates as they exploit the metal-binding properties of Aβ, forming stable interactions with the peptide, thereby limiting its aggregation and toxicity. Previously, ruthenium-based complexes have shown a strong ability to modulate the aggregation and cytotoxicity of Aβ, where the incorporation of a primary amine on the coordinated heterocyclic ligand gave the greatest activity. To determine the importance of the location of the primary amine on the pyridine ligand, thereby establishing structure-activity relationships (SAR), four complexes (RuP1-4) were prepared and evaluated for their ability to coordinate and subsequently modulate the aggregation and cytotoxicity of Aβ. Coordination to Aβ was determined using three complementary spectroscopic methods: UV-Vis, ¹H NMR, and circular dichroism (CD). Similarly, the impact of the complexes on Aβ aggregation was evaluated using three sequential methods of turbidity, dynamic light scattering (DLS), and transmission electron microscopy (TEM). Overall, the location of the primary amine on the pyridine ligand did affect the resultant anti-Aβ performance, with the 2-aminopyridine complex (RuP2) being the most active. This SAR will provide another guiding principle in the design of future metal-based anti-Aβ complexes.

Keywords: Alzheimer's disease; Amyloid-beta peptide; Ruthenium therapeutics; Structure-activity relationships.