Aβ(1-42) Assembly in the Presence of scyllo-Inositol Derivatives: Identification of an Oxime Linkage as Important for the Development of Assembly Inhibitors

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 i...

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Veröffentlicht in:ACS chemical neuroscience 2012-03, Vol.3 (3), p.167-177
Hauptverfasser: Shaw, J. E, Chio, J, Dasgupta, S, Lai, A. Y, Mo, G. C. H, Pang, F, Thomason, L. A. M, Yang, A. J, Yip, C. M, Nitz, M, McLaurin, J
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Sprache:eng
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Zusammenfassung: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.
ISSN:1948-7193
1948-7193
DOI:10.1021/cn2000926