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Lim, Mi Hee
MetalloNeuroChemistry Lab (MNCL)
Research Interests
  • Neurodegenerative disease, small molecule design, network between metal, proteins, and ROS

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

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Title
Interaction and reactivity of synthetic aminoisoflavones with metal-free and metal-associated amyloid-β
Author
Detoma, Alaina S.Krishnamoorthy, JanarthananNam, YounwooLee, Hyuck JinBrender, Jeffrey R.Kochi, AkikoLee, DongkukOnnis, ValentinaCongiu, CenzoManfredini, StefanoVertuani, SilviaBalboni, GianfrancoRamamoorthy, AyyalusamyLim, Mi Hee
Issue Date
2014-12
Publisher
ROYAL SOC CHEMISTRY
Citation
CHEMICAL SCIENCE, v.5, no.12, pp.4851 - 4862
Abstract
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 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 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 of prefibrillar Aβ, 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 Aβ and enthalpy/entropy balance for their Aβ interaction. 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 into the requirements for parity among metal chelation, intermolecular interactions, and substituent variation for Aβ interaction.
URI
https://scholarworks.unist.ac.kr/handle/201301/8983
URL
http://www.scopus.com/inward/record.url?partnerID=HzOxMe3b&scp=84908405947
DOI
10.1039/c4sc01531b
ISSN
2041-6520
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