Rational Design of η⁶-Arene Ru(II) Complexes for Amyloid-β Targeting: Influence of Coordination Lability and Aromaticity

Abstract

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 (Aβ₁–₄₂ and Aβ₂₁–₄₀) 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 Aβ₁–₄₂ fibrillization, whereas the neutral, dichloro complex RuCl₂Tol exhibited enhanced efficacy toward the shorter Aβ₂₁–₄₀ 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 Aβ₁–₄₂-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