Strategic Design of 2,2'-Bipyridine Derivatives to Modulate Metal-Amyloid-ß Aggregation.

The complexity of Alzheimer's disease (AD) stems from the inter-relation of multiple pathological factors upon initiation and progression of the disease. To identify the involvement of metal-bound amyloid-ß (metal-Aß) aggregation in AD pathology, among the pathogenic features found in the AD-affected brain, small molecules as chemical tools capable of controlling metal-Aß aggregation were developed. Herein, we report a new class of 2,2'-bipyridine (bpy) derivatives (1-4) rationally designed to be chemical modulators toward metal-Aß aggregation over metal-free Aß analogue. The bpy derivatives were constructed through a rational design strategy employing straightforward structural variations onto the backbone of a metal chelator, bpy: (i) incorporation of an Aß interacting moiety; (ii) introduction of a methyl group at different positions. The newly prepared bpy derivatives were observed to bind to metal ions [i.e., Cu(II) and Zn(II)] and interact with metal-Aß over metal-free Aß to varying degrees. Distinguishable from bpy, the bpy derivatives (1-3) were indicated to noticeably modulate the aggregation pathways of Cu(II)-Aß and Zn(II)-Aß over metal-free Aß. Overall, our studies of the bpy derivatives demonstrate that the alteration of metal binding properties as well as the installation of an Aß interacting capability onto a metal chelating framework, devised via the rational structure-based design, were able to achieve evident modulating reactivity against metal-Aß aggregation. Obviating the need for complicated structures, our design approach, presented in this work, could be appropriately utilized for inventing small molecules as chemical tools for studying desired metal-related targets in biological systems.

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

Amyloid-ß (Aß) accumulation, metal ion dyshomeostasis, oxidative stress, and cholinergic deficit are four major characteristics of Alzheimer's disease (AD). Herein, we report the reactivities of 12 flavonoids against four pathogenic elements of AD: metal-free and metal-bound Aß, free radicals, and acetylcholinesterase. A series of 12 flavonoids was selected based on the molecular structures that are responsible for multiple reactivities including hydroxyl substitution and transfer of the B ring from C2 to C3. Our experimental and computational studies reveal that the catechol moiety, the hydroxyl groups at C3 and C7, and the position of the B ring are important for instilling multiple functions in flavonoids. We establish a structure-activity relationship of flavonoids that should be useful for designing chemical reagents with multiple reactivities against the pathological factors of AD.

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

We report orobol as a multifunctional isoflavone with the ability to (i) modulate the aggregation pathways of both metal-free and metal-bound amyloid-ß, (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.

Structure-mechanism-based engineering of chemical regulators targeting distinct pathological factors in Alzheimer's disease.

The absence of effective therapeutics against Alzheimer's disease (AD) is a result of the limited understanding of its multifaceted aetiology. Because of the lack of chemical tools to identify pathological factors, investigations into AD pathogenesis have also been insubstantial. Here we report chemical regulators that demonstrate distinct specificity towards targets linked to AD pathology, including metals, amyloid-ß (Aß), metal-Aß, reactive oxygen species, and free organic radicals. We obtained these chemical regulators through a rational structure-mechanism-based design strategy. We performed structural variations of small molecules for fine-tuning their electronic properties, such as ionization potentials and mechanistic pathways for reactivity towards different targets. We established in vitro and/or in vivo efficacies of the regulators for modulating their targets' reactivities, ameliorating toxicity, reducing amyloid pathology, and improving cognitive deficits. Our chemical tools show promise for deciphering AD pathogenesis and discovering effective drugs.