Strategic Design of 2,2′-Bipyridine Derivatives to Modulate Metal–Amyloid‑β 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-β (metal-Aβ) aggregation in AD pathology, among the pathogenic features found in the AD-affected brain, small molecules as chemical tools capable of controlling metal–Aβ aggregation were developed. Herein, we report a new class of 2,2′-bipyridine (<b>bpy</b>) derivatives (<b>1</b>–<b>4</b>) rationally designed to be chemical modulators toward metal–Aβ aggregation over metal-free Aβ analogue. The <b>bpy</b> derivatives were constructed through a rational design strategy employing straightforward structural variations onto the backbone of a metal chelator, <b>bpy</b>: (i) incorporation of an Aβ interacting moiety; (ii) introduction of a methyl group at different positions. The newly prepared <b>bpy</b> derivatives were observed to bind to metal ions [i.e., Cu­(II) and Zn­(II)] and interact with metal–Aβ over metal-free Aβ to varying degrees. Distinguishable from <b>bpy</b>, the <b>bpy</b> derivatives (<b>1</b>–<b>3</b>) were indicated to noticeably modulate the aggregation pathways of Cu­(II)–Aβ and Zn­(II)–Aβ over metal-free Aβ. Overall, our studies of the <b>bpy</b> derivatives demonstrate that the alteration of metal binding properties as well as the installation of an Aβ interacting capability onto a metal chelating framework, devised via the rational structure-based design, were able to achieve evident modulating reactivity against metal–Aβ 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.