Development of bifunctional stilbene derivatives for targeting and modulating metal-amyloid-? species.

ABSTRACT: 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.

SUBMITTER: Braymer JJ 

PROVIDER: S-EPMC3437264 | biostudies-literature | 2011 Nov

REPOSITORIES: biostudies-literature