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

DeToma AS;Krishnamoorthy J;Nam Y;Lee HJ;Brender JR;Kochi A;Lee D;ONNIS, VALENTINA;CONGIU, CENZO;Manfredini S;Vertuani S;BALBONI, GIANFRANCO;Ramamoorthy A;Lim MH

2014-01-01

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Abstract

Metal ion homeostasis in conjunction with amyloid-b (Ab) 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 modulate both metal-free and metal-induced Ab 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 Ab, we designed, synthesized, and characterized a set of isoflavone derivatives, aminoisoflavones (1–4), that displayed reactivity (i.e., modulation of Ab aggregation) in vitro. NMR studies revealed a potential binding site for aminoisoflavones between the N-terminal loop and central helix of prefibrillar Ab, which is 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 Ab. Furthermore, having a catechol group influenced the binding mode with fibrillar Ab. Inclusion of additional substituents moderately tuned the impact of aminoisoflavones on Ab aggregation. Overall, through these studies, we obtained valuable insights into the requirements for parity among metal chelation, intermolecular interactions, and substituent variation for Ab interaction.