Ruthenium(III) complexes containing thiazole-based ligands that modulate amyloid-β aggregation

Alzheimer's Disease (AD) is a devastating neurodegenerative disorder where one of the commonly observed pathological hallmarks is extracellular deposits of the peptide amyboid-beta (A beta). These deposits contain a high concentration of metals and initially presented a promising target for therapy; however it has become increasingly evident that the soluble form of the peptide is neurotoxic, not the amyboidogenic species. Metal-based therapeutics are uniquely suited to target soluble A beta and have shown considerable promise to prevent the aggregation and induced cytotoxicity of the peptide in vitro. Herein, we have prepared a small series of derivatives of two promising Ru(III) complexes NAMI-A (imidazolium [trans-RuCl4(1H-imidazole)(dimethyl sulfoxide-S)]) and PMRU20 (2-aminothiazohum [trans-RuCl4(2-aminothiazole)(2)]), to determine structure-activity relationships (SAR) for Ru(III) therapeutics for AD. Using the three complementary methods of Thioflavin T fluorescence, dynamic Eight scattering (DLS), and transmission electron microscopy (TEM), it was determined that the symmetry around the metal center did not significantly impact the activity of the complexes, but rather the attached thiazole Eigand(s) mitigated A beta aggregation. Across both families of Ru(III) complexes the determined SAR for the functional groups on the thiazole ligands to modulate A beta aggregation were NH2 > CH3 > H. These results highlight the importance of secondary interactions between the metaotherapeutic and the A beta peptide where hydrogen-bonding has the greatest impact on modulating A beta aggregation.