Rational design of η⁶-arene Ru(II) complexes for amyloid-β targeting: influence of coordination lability and...

The interaction of transition-metal complexes with amyloidogenic peptides represents a promising strategy for controlling pathological protein aggregation through coordination chemistry and supramolecular effects. Herein, we investigate a series of η⁶-arene Ru(II) complexes bearing a glucosylated N-heterocyclic carbene (NHC) ligand and distinct ancillary ligand environments as modulators of amyloid-β (Aβ_1-42 and Aβ_21-40) aggregation. By systematically varying the nature of the arene, overall charge, and ligands lability, we elucidate how the design of the complexes governs peptide binding, aggregation pathways, fibril morphology, and cytotoxicity. Thioflavin T fluorescence assay revealed pronounced, peptide-dependent inhibition of amyloid aggregation. RuPhenCym strongly suppresses Aβ_1-42 fibrillization, whereas the neutral, dichloro complex RuCl2Tol exhibited enhanced efficacy toward the shorter Aβ_21-40 fragment. Circular dichroism spectroscopy demonstrated that Ru complexes modulate peptide secondary structure, promoting early β-structured species formation and altering aggregation kinetics. Scanning electron microscopy showed substantial remodeling of fibril morphology, including reduced fiber length and increased heterogeneity, indicative of off-pathway aggregation. Electrospray ionization mass spectrometry provided direct evidence of adducts formation in the presence of RuCl2Tol, highlighting the crucial role of labile chloride ligands in generating coordination vacancies that enable peptide binding. Importantly, RuCl2Tol and RuPhenCym significantly attenuate Aβ_1-42-induced cytotoxicity in SH-SY5Y neuroblastoma cells without exhibiting intrinsic cellular toxicity. Overall, this study establishes clear structure-activity relationships linking ligand environment, coordination chemistry, and biological outcome in η⁶-arene Ru(II)-amyloid systems. These findings identify glucosylated η⁶-arene Ru(II) complexes as tunable bioinorganic platforms for the selective modulation of amyloid aggregation, providing a rational framework for the development of metal-based agents targeting neurodegenerative disorders.