Synthetic Flavonoids, Aminoisoflavones: Interaction and Reactivity with Metal-Free and Metal-Associated Amyloid-? Species.

ABSTRACT: Metal ion homeostasis in conjunction with amyloid-? (A?) aggregation in the brain has been implicated in Alzheimer's disease (AD) pathogenesis. To uncover the interplay between metal ions and A? peptides, synthetic, multifunctional small molecules have been employed to modulate A? aggregation in vitro. Naturally occurring flavonoids have emerged as a valuable class of compounds for this purpose due to their ability to modulate both metal-free and metal-induced A? aggregation. Although, flavonoids have shown anti-amyloidogenic effects, the structural moieties of flavonoids responsible for such reactivity have not been fully identified. In order to understand the structure-interaction-reactivity relationship within the flavonoid family for metal-free and metal-associated A?, we designed, synthesized, and characterized a set of isoflavone derivatives, aminoisoflavones (1-4), that displayed reactivity (i.e., modulation of A? aggregation) in vitro. NMR studies revealed a potential binding site for aminoisoflavones between the N-terminal loop and central helix on prefibrillar A? different from the non-specific binding observed for other flavonoids. The absence or presence of the catechol group differentiated the binding affinities and enthalpy/entropy balance between aminoisoflavones and A?. Furthermore, having a catechol group influenced the binding mode with fibrillar A?. Inclusion of additional substituents moderately tuned the impact of aminoisoflavones on A? aggregation. Overall, through these studies, we obtained valuable insights on the requirements for parity among metal chelation, intermolecular interactions, and substituent variation for A? interaction.

SUBMITTER: DeToma AS 

PROVIDER: S-EPMC4217218 | biostudies-literature | 2014 Dec

REPOSITORIES: biostudies-literature