Small Molecule Modulators of Copper-Induced A beta Aggregation

(Chemical Equation Presented) Our design of bifunctional metal chelators as chemical probes and potential therapeutics for Alzheimer's disease (AD) is based on the incorporation of a metal binding moiety into structural frameworks of A?? aggregate-imaging agents. Using this strategy, two compounds 2-[4-(dimethylamino)phenyl]imidazo[1,2-a]pyridine-8-ol (1) and N 1,N1-dimethyl-N4-(pyridin-2-ylmethylene) benzene-1,4-diamine (2) were prepared and characterized. The bifunctionality for metal chelation and A?? interaction of 1 and 2 was verified by spectroscopic methods. Furthermore, the reactivity of 1 and 2 with Cu II-associated A?? aggregates was investigated. The modulation of CuII-triggered A?? aggregation by 1 and 2 was found to be more effective than that by the known metal chelating agents CQ, EDTA, and phen. These studies suggest a new class of multifunctional molecules for the development of chemical tools to unravel metal-associated events in AD and potential therapeutic agents for metal-ion chelation therapy.close919

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

Amyloid-?? (A??) 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-A?? 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-A?? species have been developed, which could serve as suitable chemical tools for investigating metal-A??-associated events in AD. Through a rational structure-based design principle involving the incorporation of a metal binding site into the structure of an A?? interacting molecule, we devised stilbene derivatives (L1-a and L1-b) and demonstrated their reactivity toward metal-A?? 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 A?? aggregation and neurotoxicity in vitro and in living cells. Mechanistic investigations of the reaction of L1-a and L1-b with Zn 2+-A?? species by UV-vis and 2D NMR suggest that metal chelation with ligand and/or metal-ligand interaction with the A?? peptide may be driving factors for the observed modulation of metal-A?? aggregation pathways. Overall, the studies presented herein demonstrate the importance of a structure-interaction-reactivity relationship for designing small molecules to target metal-A?? species allowing for the modulation of metal-induced A?? reactivity and neurotoxicity.close443