title: Synthesis and characterization of IMPY derivatives that regulate metal-induced amyloid-β aggregation.
abstract: Metal ions associated with amyloid-β (Aβ) species have been suggested to be involved in neurodegeneration leading to the progression of Alzheimer's disease (AD). The role of metal-involved Aβ species in AD neuropathogenesis, however, is not fully elucidated. In order to advance this understanding and contribute to the therapeutic development for AD, the rational structure-based design of small molecules that specifically target metal ions surrounded by Aβ species has recently received increased attention. To date, only a few compounds have been fashioned for this purpose. Herein, we report the design strategy, synthesis, characterization, and reactivity of new bifunctional IMPY derivatives K1 and K2. Using UV-vis and high-resolution two-dimensional (2D) NMR spectroscopy, the bifunctionality of K1 and K2 (metal chelation and Aβ interaction) was confirmed. These bifunctional IMPY derivatives showed preferential reactivity toward metal-induced Aβ aggregation over metal-free conditions in both in vitro inhibition and disaggregation experiments. Taken together, this study provides another example of a bifunctional small molecule framework that can target metal ions associated with Aβ species.
authors.affiliation: Life Sciences Institute, University of Michigan, Ann Arbor, Michigan 48109-2216, USA.
authors.forename: Jung-Suk
authors.initials: JS
authors.lastname: Choi
authors.forename: Joseph J
authors.initials: JJ
authors.lastname: Braymer
authors.forename: Se Kyung
authors.initials: SK
authors.lastname: Park
authors.forename: Shaik
authors.initials: S
authors.lastname: Mustafa
authors.forename: Junghyun
authors.initials: J
authors.lastname: Chae
authors.forename: Mi Hee
authors.initials: MH
authors.lastname: Lim
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy* / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000378:metabolism* / Q000648:ultrastructure; D002614:Chelating Agents / Q000737:chemistry* / Q000494:pharmacology*; D015195:Drug Design; D006801:Humans; D008670:Metals / Q000378:metabolism*; D011720:Pyrazoles / Q000737:chemistry; D011725:Pyridines / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: C473191:6-iodo-2-(4'-dimethylamino-)phenyl-imidazo(1,2-a)pyridine; D016229:Amyloid beta-Peptides; D002614:Chelating Agents; D008670:Metals; D011720:Pyrazoles; D011725:Pyridines; C000971:2,3-dihydro-1H-imidazo(1,2-b)pyrazole