title: Development of bifunctional stilbene derivatives for targeting and modulating metal-amyloid-β species.
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.
authors.affiliation: Department of Chemistry, University of Michigan, Ann Arbor, Michigan 48109, USA.
authors.forename: Joseph J
authors.initials: JJ
authors.lastname: Braymer
authors.forename: Jung-Suk
authors.initials: JS
authors.lastname: Choi
authors.forename: Alaina S
authors.initials: AS
authors.lastname: DeToma
authors.forename: Chen
authors.initials: C
authors.lastname: Wang
authors.forename: Kisoo
authors.initials: K
authors.lastname: Nam
authors.forename: Jeffrey W
authors.initials: JW
authors.lastname: Kampf
authors.forename: Ayyalusamy
authors.initials: A
authors.lastname: Ramamoorthy
authors.forename: Mi Hee
authors.initials: MH
authors.lastname: Lim
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism* / Q000503:physiopathology; D016229:Amyloid beta-Peptides / Q000737:chemistry / Q000378:metabolism*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002614:Chelating Agents / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D003300:Copper / Q000737:chemistry / Q000378:metabolism; D018360:Crystallography, X-Ray; D015195:Drug Design; D006801:Humans; D007501:Iron / Q000737:chemistry / Q000378:metabolism; D008024:Ligands; D009682:Magnetic Resonance Spectroscopy; D046529:Microscopy, Electron, Transmission; D008958:Models, Molecular; D015335:Molecular Probes / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D011487:Protein Conformation / Q000187:drug effects; D013267:Stilbenes / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D013329:Structure-Activity Relationship; D015032:Zinc / Q000737:chemistry / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D002614:Chelating Agents; D008024:Ligands; D015335:Molecular Probes; D013267:Stilbenes; D003300:Copper; D007501:Iron; D015032:Zinc