Development of Bifunctional Stilbene Derivatives for Targeting and Modulating Metal-Amyloid-β Species

Abstract

Amyloid-β (Aβ) peptides and their metal-associated aggregated states have been implicated in the pathogenesis of Alzheimer’s disease (AD). Although the etiology of AD remains uncertain, understanding the role of metal-Aβ species could provide insights into the onset and development of the disease. To unravel this, bifunctional small molecules that can specifically target and modulate metal-Aβ species have been developed, which could serve as suitable chemical tools for investigating metal-Aβ-associated events in AD. Through a rational structure-based design principle involving the incorporation of a metal binding site into the structure of an Aβ interacting molecule, we devised stilbene derivatives (<b>L1-a</b> and <b>L1-b</b>) and demonstrated their reactivity toward metal-Aβ species. In particular, the dual functions of compounds with different structural features (e.g., with or without a dimethylamino group) were explored by UV–vis, X-ray crystallography, high-resolution 2D NMR, and docking studies. Enhanced bifunctionality of compounds provided greater effects on metal-induced Aβ aggregation and neurotoxicity in vitro and in living cells. Mechanistic investigations of the reaction of <b>L1-a</b> and <b>L1-b</b> with Zn²⁺-Aβ species by UV–vis and 2D NMR suggest that metal chelation with ligand and/or metal–ligand interaction with the Aβ peptide may be driving factors for the observed modulation of metal-Aβ aggregation pathways. Overall, the studies presented herein demonstrate the importance of a structure-interaction-reactivity relationship for designing small molecules to target metal-Aβ species allowing for the modulation of metal-induced Aβ reactivity and neurotoxicity