Enhancing the Amyloid-β Anti-Aggregation Properties of Curcumin via Arene-Ruthenium(II) Derivatization

Abstract

Alzheimer’s disease (AD) is a fatal neurodegenerative disorder associated with severe dementia, progressive cognitive decline, and irreversible memory loss. Although its etiopathogenesis is still unclear, the aggregation of amyloid-β (Aβ) peptides into supramolecular structures and their accumulation in the central nervous system play a critical role in the onset and progression of the disease. On such a premise, the inhibition of the early stages of Aβ aggregation is a potential prevention strategy for the treatment of AD. Since several natural occurring compounds, as well as metal-based molecules, showed promising inhibitory activities toward Aβ aggregation, we herein characterized the interaction of an organoruthenium derivative of curcumin with Aβ(1–40) and Aβ(1–42) peptides, and we evaluated its ability to inhibit the oligomerization/fibrillogenesis processes by combining in silico and in vitro methods. In general, besides being less toxic to neuronal cells, the derivative preserved the amyloid binding ability of the parent compound in terms of equilibrium dissociation constants but (most notably) was more effective both in retarding the formation and limiting the size of amyloid aggregates by virtue of a higher hindering effect on the amyloid–amyloid elongation surface. Additionally, the complex protected neuronal cells from amyloid toxicity.

An Overview of the Potential Medicinal and Pharmaceutical Properties of Ru(II)/(III) Complexes

“…Recently, an investigation of differences between compounds 57 and 58 (Figure 21 The density functional theory (DFT) calculations and in vitro experiments confirmed that the arene Ru(II) complex with curcumin 49 (Figure 17) is capable of inhibiting the accumulation of two β-amyloid molecules: one peptide composed of 1-40 amino acids and another composed of 1-42 amino acids. The final results indicate that complex 49 moderately affects the aggregation of β-amyloid through the hindering effect [86].…”

The Strategies of Development of New Non-Toxic Inhibitors of Amyloid Formation

“…It has been shown that a number of low molecular weight natural products, such as polyphenols (resveratrol, quercetin) inhibited Aβ amyloid aggregation [ 109 , 110 ]. Cuccioloni et al demonstrated that organoruthenium derivative of curcumin (RuCurcumin) inhibited the formation of Aβ aggregates and also protected nerve cells from the toxic effects of amyloids [ 111 ]. Fu et al demonstrated that curcumin and resveratrol block the oligomerization process by interacting with the N-terminus (residues 5–20) of Aβ(1–42) oligomers along with disruption of the preformed Aβ aggregates [ 109 ].…”