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Lim, Mi Hee
MetalloNeuroChemistry Lab (MNCL)
Research Interests
  • Neurodegenerative disease, small molecule design, network between metal, proteins, and ROS

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Development of Bifunctional Stilbene Derivatives for Targeting and Modulating Metal-Amyloid-beta Species

Cited 44 times inthomson ciCited 32 times inthomson ci
Title
Development of Bifunctional Stilbene Derivatives for Targeting and Modulating Metal-Amyloid-beta Species
Author
Braymer, Joseph J.Choi, Jung-SukDeToma, Alaina S.Wang, ChenNam, KisooKampf, Jeffrey W.Ramamoorthy, AyyalusamyLim, Mi Hee
Keywords
WATER-MICELLE ENVIRONMENT; ALZHEIMERS-DISEASE; A-BETA; OXIDATIVE STRESS; BINDING SURFACE; TRANSGENIC MICE; ZINC-BINDING; PEPTIDE; NMR; AGGREGATION
Issue Date
2011-11
Publisher
AMER CHEMICAL SOC
Citation
INORGANIC CHEMISTRY, v.50, no.21, pp.10724 - 10734
Abstract
Amyloid-β (Aβ) peptides and their metal-associated aggregated states have been implicated in the pathogenesis of Alzheimer's disease (AD). Although the etiology of AD remains uncertain, understanding the role of metal-Aβ species could provide insights into the onset and development of the disease. To unravel this, bifunctional small molecules that can specifically target and modulate metal-Aβ species have been developed, which could serve as suitable chemical tools for investigating metal-Aβ-associated events in AD. Through a rational structure-based design principle involving the incorporation of a metal binding site into the structure of an Aβ interacting molecule, we devised stilbene derivatives (L1-a and L1-b) and demonstrated their reactivity toward metal-Aβ species. In particular, the dual functions of compounds with different structural features (e.g., with or without a dimethylamino group) were explored by UV-vis, X-ray crystallography, high-resolution 2D NMR, and docking studies. Enhanced bifunctionality of compounds provided greater effects on metal-induced Aβ aggregation and neurotoxicity in vitro and in living cells. Mechanistic investigations of the reaction of L1-a and L1-b with Zn 2+-Aβ species by UV-vis and 2D NMR suggest that metal chelation with ligand and/or metal-ligand interaction with the Aβ peptide may be driving factors for the observed modulation of metal-Aβ aggregation pathways. Overall, the studies presented herein demonstrate the importance of a structure-interaction-reactivity relationship for designing small molecules to target metal-Aβ species allowing for the modulation of metal-induced Aβ reactivity and neurotoxicity.
URI
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DOI
10.1021/ic2012205
ISSN
0020-1669
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PHY_Journal Papers
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