Heterobimetallic ferrocenyl-chromone compounds as selective inhibitors of amyloid aggregation

Amyloid aggregation is a key process in neurodegeneration, producing toxic species that contribute to disease progression. This underscores the urgent need to identify novel agents capable of reducing toxicity by modulating this aggregation process. Two heterobimetallic complexes incorporating a ferrocenyl-chromone (Fc-Chr) core were investigated: one featuring an additional gold(I) triphenylphosphine moiety, Fc-Chr-AuP(Ph)₃, and the other containing a dicobalt hexacarbonyl-alkyne unit, Fc-Chr-Co₂(CO)₆. Their effects were evaluated toward on the aggregation of two amyloid models: the peptide spanning residues 264–277 of nucleophosmin 1 (NPM1264–277) and the C-terminal fragment of the amyloid-β peptide (Aβ21–40) each with unique primary sequences, self-aggregation mechanisms and kinetics. Thioflavin T- assays allowed to assess the impact of the metal complexes on the aggregation of two amyloids. Results indicate that the two complexes inhibit the early stages of the aggregation of peptides in a dose-dependent manner and a greater effect on NPM1264–277 when compared to Aβ21–40 was observed. Native electrospray ionization mass spectrometry revealed the formation of peculiar metal/peptide adducts in dependence on different metal-units in the complexes. Scanning electron microscopy (SEM) and density function theory (DFT) were also employed to further characterize the interaction between the metal compounds and the investigated peptides, while preliminary cell viability assays in SH-SY5Y cells supported inhibitory effects on the aggregation and showed reduction of amyloid cytotoxicity. Fc-Chr-Co₂(CO)₆ demonstrated the highest efficacy in modulating peptide aggregation, exerting a more significant impact on NMP1264–277 relative to Aβ₂₁₋₄₀. These results support the use of ferrocenyl-chromone containing metal complexes as modulators of amyloid peptide aggregation.