Alzheimer’s disease (AD) is the most common neurodegenerative disorder and, prior to the COVID-19 pandemic, the sixth leading cause of death in the United States. One of the disease hallmarks are protein deposits around neurons, the main component of which is the amyloid-beta (Aβ) peptide. The Aβ peptide is known to aggregate spontaneously and has been shown to bind redox-active metals, promoting its aggregation and cytotoxicity to the surrounding neurons. Previous work has shown success in the disruption of Aβ aggregation through the use of ruthenium(III) complexes. Data indicates that the peptide coordinates to the Ru(III) center, keeping the peptide in solution, limiting its aggregation. These complexes, containing an azole ligand, show the most dramatic increase in activity with the addition of an amine group to the ligand. Our goal is to further develop structure-activity relationships for Ru(III) complexes by altering the ligands attached. A series of complexes with attached pyridine ligands containing an amine group have been synthesized to provide a broader view of the possibilities of Ru(III) complexes as Alzheimer’s disease therapeutics. The ability of the complexes to modulate the aggregation of the Aβ peptide was evaluated using dynamic light scattering (DLS), Thioflavin T fluorescence, and transmission electron microscopy (TEM). The results of the assays and the structure-activity relationships identified will be discussed.

Synthesis, characterization and analysis of structure-activity relationships of ruthenium-based Alzheimer’s disease therapeutics

ACS Spring Meeting 2021

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