Orobol: An Isoflavone Exhibiting Regulatory Multifunctionality against Four Pathological Features of Alzheimer’s Disease

Abstract

We report orobol as a multifunctional isoflavone with the ability to (i) modulate the aggregation pathways of both metal-free and metal-bound amyloid-β, (ii) interact with metal ions, (iii) scavenge free radicals, and (iv) inhibit the activity of acetylcholinesterase. Such a framework with multifunctionality could be useful for developing chemical reagents to advance our understanding of multifaceted pathologies of neurodegenerative disorders, including Alzheimer’s disease.

Amentoflavone: A Bifunctional Metal Chelator that Controls the Formation of Neurotoxic Soluble Aβ42 Oligomers

“…33,38 A strategy has been the search for such bifunctional chelators among naturallyoccurring compounds, and flavonoid compounds have been shown to interact with amyloidogenic peptides and arrest or redirect aggregation pathways. [39][40][41][42][43][44][45][46] For example, the green tea extracts (-)epigallocatechin-3-gallate (EGCG) and myricetin inhibit metal-induced Aβ40 aggregation by forming EGCG-metal-Aβ40 complexes. 39,47 We and others have previously found that the naturally-occurring biflavonoids including amentoflavone (AMF) potently attenuate Aβ aggregation and cytotoxicity, [48][49][50] however the metal-chelating ability of AMF and its effect on Aβ aggregation in presence of metal ions has not been investigated to date.…”

Reactivity of Flavonoids Containing a Catechol or Pyrogallol Moiety with Metal‐Free and Metal‐Associated Amyloid‐β

“…Nam et al . reported multiple reactivities of orobol toward the pathological factors found in AD, including metal‐free Aβ 42 , metal–Aβ 42 , free radicals, and acetylcholinesterase 64,65 . Notably, orobol impacted the aggregation of both metal‐free and metal‐associated Aβ 42 .…”

“…Orobol , as depicted in Figure 4(a), that is an isoflavone with a catechol moiety was evaluated for its reactivity against metal‐free and metal‐induced Aβ aggregation 64,65 . Nam et al .…”

Multiple reactivities of flavonoids towards pathological elements in Alzheimer's disease: structure–activity relationship

“…27,28 Oro was found to interact with metal ions, alter the aggregation of both metal-free and metal-bound Ab, scavenge free radicals, and inhibit the catalytic activity of AChE. 29,30 The 12 avonoids enumerated in Fig. 1 include three different classes, namely avonols (row 1), avones (row 2), and iso-avones (row 3), that offer signicant structural variance.…”