Ruthenium(III) complexes with imidazole ligands that modulate the aggregation of the amyloid-ß peptide via hydrophobic interactions.

Alzheimer's disease (AD) is the most common form of dementia, characterized by extracellular protein deposits, comprised primarily of the peptide amyloid-beta (Aß), are a pathological indicator of the disease. Commonly known as Aß plaques, these deposits contain a relatively high concentration of metals, making metallotherapeutics uniquely suited to target soluble Aß, thereby limiting its aggregation and cytotoxicity. Ruthenium-based complexes are promising candidates for advancement, as the complex PMRU20 (2-aminothiazolium [trans-RuCl4(2-aminothiazole)2]) and several thiazole-based derivatives were found to prevent the aggregation of Aß, with hydrogen-bonding functional groups improving their performance. Further investigation into the impact of the heteroatom in the azole ring on the activity of Ru complexes was achieved through the synthesis and evaluation of a small set of imidazole-based compounds. The ability of the complexes to prevent the aggregation of Aß was determined where the same sample was subjected to analysis by three complementary methods: ThT fluorescence, dynamic light scattering (DLS), and transmission electron microscopy (TEM). It was found that hydrophobic interactions, along with hydrogen-bonding via the imidazole nitrogen heteroatom, promoted interactions with the Aß peptide, thereby limiting its aggregation. Furthermore, it was found that having rapid and sequential exchange proved detrimental as it resulted in a decreased association with Aß. These results highlight important considerations between a balance of intermolecular interactions and ligand exchange kinetics in the design of further therapeutic candidates.

Ruthenium(iii) complexes containing thiazole-based ligands that modulate amyloid-ß aggregation.

Alzheimer's Disease (AD) is a devastating neurodegenerative disorder where one of the commonly observed pathological hallmarks is extracellular deposits of the peptide amyloid-ß (Aß). 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 amyloidogenic species. Metal-based therapeutics are uniquely suited to target soluble Aß 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-aminothiazolium [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 light 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 ligand(s) mitigated Aß aggregation. Across both families of Ru(iii) complexes the determined SAR for the functional groups on the thiazole ligands to modulate Aß aggregation were NH2 > CH3 > H. These results highlight the importance of secondary interactions between the metallotherapeutic and the Aß peptide where hydrogen-bonding has the greatest impact on modulating Aß aggregation.