title: Aβ(1-42) assembly in the presence of scyllo-inositol derivatives: identification of an oxime linkage as important for the development of assembly inhibitors.
abstract: To identify a lead skeleton structure for optimization of scyllo-inositol-based inhibitors of amyloid-beta peptide (Aβ) aggregation, we have synthesized aldoxime, hydroxamate, carbamate, and amide linked scyllo-inositol derivatives. These structures represent backbones that can be readily expanded into a wide array of derivatives. They also provide conservative modifications of the scyllo-inositol backbone, as they maintain the display of the equatorial polar atoms, preserving the stereochemical requirement necessary for maximum inhibition of Aβ(1-42) fiber formation. In addition, a reliable work plan for screening derivatives was developed in order to preferentially identify a backbone(s) structure that prevents fibrillogenesis and stabilizes nontoxic small molecular weight oligomers, as we have previously reported for scyllo-inositol. In the present studies, we have adapted a high throughput ELISA-based oligomerization assay followed by atomic force microscopy to validate the results screen compounds. The lead compounds were then tested for toxicity and ability to rescue Aβ(1-42) induced toxicity in vitro and the affinity of the compounds for Aβ(1-42) compared by mass spectrometry. The data to suggest that compounds must maintain a planar conformation to exhibit activity similar to scyllo-inositol and that the oxime derivative represents the lead backbone for future development.
authors.affiliation: Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada.
authors.forename: J E
authors.initials: JE
authors.lastname: Shaw
authors.forename: J
authors.initials: J
authors.lastname: Chio
authors.forename: S
authors.initials: S
authors.lastname: Dasgupta
authors.forename: A Y
authors.initials: AY
authors.lastname: Lai
authors.forename: G C H
authors.initials: GC
authors.lastname: Mo
authors.forename: F
authors.initials: F
authors.lastname: Pang
authors.forename: L A M
authors.initials: LA
authors.lastname: Thomason
authors.forename: A J
authors.initials: AJ
authors.lastname: Yang
authors.forename: C M
authors.initials: CM
authors.lastname: Yip
authors.forename: M
authors.initials: M
authors.lastname: Nitz
authors.forename: J
authors.initials: J
authors.lastname: McLaurin
mesh_terms: D000682:Amyloid / Q000737:chemistry / Q000187:drug effects; D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D045744:Cell Line, Tumor; D006801:Humans; D007294:Inositol / Q000737:chemistry / Q000494:pharmacology*; D010091:Oximes / Q000737:chemistry / Q000494:pharmacology*; D010446:Peptide Fragments / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D011487:Protein Conformation / Q000187:drug effects
chemical_list: D000682:Amyloid; D016229:Amyloid beta-Peptides; D010091:Oximes; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42); C009217:scyllitol; D007294:Inositol