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

Abstract

Metal ions associated with amyloid-beta (A beta) 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 A beta 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 FL1-FL4 were rationally selected according to the principles of bifunctionality and their abilities to chelate metal ions, interact with A beta, inhibit metal-induced A beta aggregation, scavenge radicals, and regulate the formation of reactive oxygen species (ROS) were studied using physical methods and biological assays. The compounds FL1-FL3 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 mu M, respectively) were obtained through solution speciation studies. The direct interaction between FL4 and A beta monomer was weak, which was monitored by NMR spectroscopy and mass spectrometry. Employing FL1-FL4, no noticeable inhibitory effect on metal-mediated A beta aggregation was observed. Among FL1-FL4, 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+-A beta in the presence of dioxygen (O-2) and a reducing agent. Overall, the studies here suggest that although four flavonoid molecules were selected based on expected bifunctionality, their properties and metal-A beta reactivity were varied depending on the structure differences, demonstrating that bifunctionality must be well tuned to afford desirable reactivity.