Synthetic Flavonoids, Aminoisoflavones: Interaction and Reactivity with Metal-Free and Metal-Associated Amyloid-β Species.
Metal ion homeostasis in conjunction with amyloid-β (Aβ) aggregation in the brain has been implicated in Alzheimer's disease (AD) pathogenesis. To uncover the interplay between metal ions and Aβ peptides, synthetic, multifunctional small molecules have been employed to modulate Aβ aggregationin 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 Aβ 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 Aβ, we designed, synthesized, and characterized a set of isoflavone derivatives, aminoisoflavones (1-4), that displayed reactivity (i.e., modulation of Aβ aggregation)in vitro. NMR studies revealed a potential binding site for aminoisoflavones between the N-terminal loop and central helix on prefibrillar Aβ 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 Aβ. Furthermore, having a catechol group influenced the binding mode with fibrillar Aβ. Inclusion of additional substituents moderately tuned the impact of aminoisoflavones on Aβ aggregation. Overall, through these studies, we obtained valuable insights on the requirements for parity among metal chelation, intermolecular interactions, and substituent variation for Aβ interaction.
Department of Chemistry, University of Michigan, Ann Arbor, Michigan 48109-1055, USA.
Alaina S
AS
DeToma
Department of Chemistry, University of Michigan, Ann Arbor, Michigan 48109-1055, USA ; Biophysics, University of Michigan, Ann Arbor, Michigan 48109-1055, USA.
Janarthanan
J
Krishnamoorthy
Life Sciences Institute, University of Michigan, Ann Arbor, Michigan 48109-2216, USA ; Department of Fine Chemistry, Seoul National University of Science and Technology, Seoul, Korea ; Department of Chemistry, Ulsan National Institute of Science and Technology (UNIST), Ulsan 689-798, Korea.
Younwoo
Y
Nam
Department of Chemistry, University of Michigan, Ann Arbor, Michigan 48109-1055, USA ; Department of Chemistry, Ulsan National Institute of Science and Technology (UNIST), Ulsan 689-798, Korea.
Hyuck Jin
HJ
Lee
Department of Chemistry, University of Michigan, Ann Arbor, Michigan 48109-1055, USA ; Biophysics, University of Michigan, Ann Arbor, Michigan 48109-1055, USA.
Jeffrey R
JR
Brender
Department of Chemistry, University of Michigan, Ann Arbor, Michigan 48109-1055, USA ; Department of Chemistry, Ulsan National Institute of Science and Technology (UNIST), Ulsan 689-798, Korea.
Akiko
A
Kochi
Department of Fine Chemistry, Seoul National University of Science and Technology, Seoul, Korea.
Dongkuk
D
Lee
Department of Life Sciences and Biotechnology, University of Ferrara, I-44121 Ferrara, Italy.
Valentina
V
Onnis
Department of Life Sciences and Biotechnology, University of Ferrara, I-44121 Ferrara, Italy.
Cenzo
C
Congiu
Department of Life and Environment Sciences, Pharmaceutical, Pharmacological and Nutraceutical Sciences Unit, University of Cagliari, I-09124 Cagliari, Italy.
Stefano
S
Manfredini
Department of Life and Environment Sciences, Pharmaceutical, Pharmacological and Nutraceutical Sciences Unit, University of Cagliari, I-09124 Cagliari, Italy.
Silvia
S
Vertuani
Department of Life Sciences and Biotechnology, University of Ferrara, I-44121 Ferrara, Italy.
Gianfranco
G
Balboni
Department of Chemistry, University of Michigan, Ann Arbor, Michigan 48109-1055, USA ; Biophysics, University of Michigan, Ann Arbor, Michigan 48109-1055, USA.
Ayyalusamy
A
Ramamoorthy
Life Sciences Institute, University of Michigan, Ann Arbor, Michigan 48109-2216, USA ; Department of Chemistry, Ulsan National Institute of Science and Technology (UNIST), Ulsan 689-798, Korea.
Mi Hee
MH
Lim