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

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 FL1 – FL4 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 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 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 FL1 – FL4, no noticeable inhibitory effect on metal-mediated Aβ 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+-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.

Copper Toxicity Links to Pathogenesis of Alzheimer’s Disease and Therapeutics Approaches

“…Currently, small novel compounds such as 2,2-bipyridine (bpy) derivatives (1–4) and other N,N-dimethylaniline including novel N-bidentate ligands, have been described to show good results for the treatment of multifactorial AD [ 304 , 305 ]. The effects of several flavonoids such as myricetin and EGCG (epigallocatechin gallate) have also been tested for this disorder [ 306 , 307 , 308 ].…”

Molecular crowding effects on the biochemical properties of amyloid β–heme, Aβ–Cu and Aβ–heme–Cu complexes

“…The produced ROS by Ab40 related complexes in the presence of a reducing agent (ascorbate) was detected using Amplex Red/ horseradish peroxidase (HRP) assays. 35 Different Ab40 related samples (5 mM) in PBS (pH 7.0) were rst mixed with HRP (1 U mL À1 ) and Amplex Red (50 mM). The formation of resorun was initiated by the addition of ascorbate (50 mM) in the reaction mixture.…”

Recent Developments in Metal-Based Drugs and Chelating Agents for Neurodegenerative Diseases Treatments

“…In this sense, a wide range of molecules has been developed, focusing on possible multitarget drugs for the treatment of AD and other NDDs. Among these drugs, there may be highlighted the molecules derived from various compounds, as triazole (TRI) ( 16 ) [164,165,166,167,168,169] diferiprone (DFP) ( 17 ) [170,171,172,173], 8-hydroxyquinoline (8-HQ) ( 18 ) [163,174,175,176,177,178], cyclam (CY) ( 19 ) [179,180,181,182,183], thioflavine T (ThT) ( 20 ) [19,184,185,186,187], p -I-stilbene (pISTIB) ( 21 ) [188,189,190,191,192,193,194,195,196], chalcone (CHAL) ( 22 ) [167,168], resveratrol (RESV) ( 23 ) [197,198], flavone (FLAV) ( 24 ) [199,200], donepezil (DONE) ( 25 ) [201,202,203,204,205], tacrine (TAC) ( 26 ) [206,207,208,209,210,211,212,213,214,215,216,217,218,219], dopamine (DOP) ( 27 ) [220] and peptide-based inhibitors (PEP) [221,…”