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

• Published in: Inorganic chemistry 2011-11, Vol.50 (21), p.10724-10734
• Main Authors: Braymer, Joseph J, Choi, Jung-Suk, DeToma, Alaina S, Wang, Chen, Nam, Kisoo, Kampf, Jeffrey W, Ramamoorthy, Ayyalusamy, Lim, Mi Hee
• Format: Article
• Language: English
• Subjects: Alzheimer Disease - metabolism; Alzheimer Disease - physiopathology; Amyloid beta-Peptides - chemistry; Amyloid beta-Peptides - metabolism; Cell Line, Tumor; Cell Survival - drug effects; Chelating Agents - chemical synthesis; Chelating Agents - metabolism; Chelating Agents - pharmacology; Copper - chemistry; Copper - metabolism; Crystallography, X-Ray; Drug Design; Humans; Iron - chemistry; Iron - metabolism; Ligands; Magnetic Resonance Spectroscopy; Microscopy, Electron, Transmission; Models, Molecular; Molecular Probes - chemical synthesis; Molecular Probes - metabolism; Molecular Probes - pharmacology; Protein Conformation - drug effects; Stilbenes - chemical synthesis; Stilbenes - metabolism; Stilbenes - pharmacology; Structure-Activity Relationship; Zinc - chemistry; Zinc - metabolism
• ISSN: 0020-1669; 1520-510X
• DOI: 10.1021/ic2012205

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 Zn2+-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.