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Issue 21, 2012
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Exploring the reactivity of flavonoid compounds with metal-associated amyloid-β species

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Abstract

Metal ions associated with amyloid-β (Aβ) peptides have been suggested to be involved in the development of Alzheimer's disease (AD), but this remains unclear and controversial. Some attempts to rationally design or select small molecules with structural moieties for metal chelation and Aβ interaction (i.e., bifunctionality) have been made to gain a better understanding of the hypothesis. In order to contribute to these efforts, four synthetic flavonoid derivatives FL1FL4 were rationally selected according to the principles of bifunctionality and their abilities to chelate metal ions, interact with Aβ, inhibit metal-induced Aβ aggregation, scavenge radicals, and regulate the formation of reactive oxygen species (ROS) were studied using physical methods and biological assays. The compounds FL1FL3 were able to chelate metal ions, but showed limited solubility in aqueous buffered solutions. In the case of FL4, which was most compatible with aqueous conditions, its binding affinities for Cu2+ and Zn2+ (nM and μM, respectively) were obtained through solution speciation studies. The direct interaction between FL4 and Aβ monomer was weak, which was monitored by NMR spectroscopy and mass spectrometry. Employing FL1FL4, no noticeable inhibitory effect on metal-mediated Aβ aggregation was observed. Among FL1FL4, FL3, having 3-OH, 4-oxo, and 4′-N(CH3)2 groups, exhibited similar antioxidant activity to the vitamin E analogue, Trolox, and ca. 60% reduction in the amount of hydrogen peroxide (H2O2) generated by Cu2+–Aβ in the presence of dioxygen (O2) and a reducing agent. Overall, the studies here suggest that although four flavonoid molecules were selected based on expected bifunctionality, their properties and metal–Aβ reactivity were varied depending on the structure differences, demonstrating that bifunctionality must be well tuned to afford desirable reactivity.

Graphical abstract: Exploring the reactivity of flavonoid compounds with metal-associated amyloid-β species

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Publication details

The article was received on 18 Nov 2011, accepted on 24 Feb 2012 and first published on 22 Mar 2012


Article type: Paper
DOI: 10.1039/C2DT12207C
Citation: Dalton Trans., 2012,41, 6558-6566

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    Exploring the reactivity of flavonoid compounds with metal-associated amyloid-β species

    X. He, H. M. Park, S. Hyung, A. S. DeToma, C. Kim, B. T. Ruotolo and M. H. Lim, Dalton Trans., 2012, 41, 6558
    DOI: 10.1039/C2DT12207C

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