Interaction and reactivity of synthetic aminoisoflavones with metal-free and metal-associated amyloid-beta

Abstract

Metal ion homeostasis in conjunction with amyloid-beta (A beta) aggregation in the brain has been implicated in Alzheimer's disease (AD) pathogenesis. To uncover the interplay between metal ions and Ab peptides, synthetic, multifunctional small molecules have been employed to modulate Ab aggregation in vitro. Naturally occurring flavonoids have emerged as a valuable class of compounds for this purpose due to their ability to control both metal-free and metal-induced A beta 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 beta, we designed, synthesized, and characterized a set of isoflavone derivatives, aminoisoflavones (1-4), that displayed reactivity (i.e., modulation of A beta aggregation) in vitro. NMR studies revealed a potential binding site for aminoisoflavones between the N-terminal loop and central helix of prefibrillar A beta, which is different from the non-specific binding observed for other flavonoids. The absence or presence of the catechol group, responsible for metal binding, differentiated the binding affinities of aminoisoflavones with A beta and enthalpy/entropy balance for their A beta interaction. Furthermore, having a catechol group influenced the binding mode with fibrillar A beta. Inclusion of additional substituents moderately tuned the impact of aminoisoflavones on A beta aggregation. Overall, through these studies, we obtained valuable insights into the requirements for parity among metal chelation, intermolecular interactions, and substituent variation for A beta interaction.