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

Strategic Design of 2,2 '-Bipyridine Derivatives to Modulate Metal Amyloid-beta Aggregation
Ji, YonghwanLee, Hyuck JinKim, MinjeongNam, GeewooLee, Shin Jung C.Cho, JaeheungPark, Cheol-MinLim, Mi Hee
DGIST Authors
Cho, Jaeheung
Issued Date
Article Type
2,2&aposDipyridylA BetaAbsorptionAlzheimer&aposs Disease (AD)ComplexesCoordinationMechanismsPeptideSmall MoleculesTarget
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 (bpy) derivatives (1-4) rationally designed to be chemical modulators toward metal-Aβ aggregation over metal-free Aβ 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 Aβ 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-Aβ over metal-free Aβ to varying degrees. Distinguishable from bpy, the bpy derivatives (1-3) 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 bpy 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. © 2017 American Chemical Society.
American Chemical Society
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Department of Physics and Chemistry Biomimetic Materials Laboratory 1. Journal Articles


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