A broad group of structurally diverse small organofluorine inhibitors have been synthesized and evaluated in the self-assembly of amyloid β. The major goal was to generate a diverse library of compounds with the same functional group and observe general structural features that characterize the oligomer and fibril inhibitors, and ultimately find lead structures for further, focused inhibitor design. The common structural motifs in these compounds were the CF3-C-OH or CF3-C-NH groups that were proposed to be a binding unit in our earlier studies. A broad range of potential small molecule inhibitors were synthesized by adding different carbocyclic and heteroaromatic rings with an array of substituents, overall 106 molecules. The compounds were tested by standard methods, such as thioflavine T-fluorescence spectroscopy for following fibril formation, biotinyl-Aβ(1–42) single-site streptavidin-based assay for observing oligomer formation and atomic force microscopy for morphological studies. These assays yielded a number of structures that showed significant inhibition against either fibril or oligomer formation. A detailed analysis on the structure activity relationship of anti-fibril and -oligomer properties is provided. In addition, these data present further experimental evidence for the distinct nature of the fibril vs oligomer formation and that the interaction of the Aβ peptide with chiral small molecules is not stereospecific in nature.
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. KEYWORDS: Amyloid-beta peptide, fibrillogenesis, medicinal chemistry, atomic force microscopy, mass spectrometry scyllo-Inositol, a potential therapeutic compound for Alzheimer's disease, has been shown to inhibit Aβ(1-42) fibrillogenesis in vitro, 1 stabilize cell-derived small molecular weight oligomers, 2 reduce amyloid plaque load and neuroinflammation, and ameliorate cognitive deficits in vivo. 2,3 These combined studies demonstrated that scyllo-inositol stabilizes low molecular weight oligomers of Aβ that are nontoxic and readily removed from and/or degraded within the central nervous system. scyllo-Inositol is the most potent inositol, with a single epimerization to form myo-inositol yielding a less active compound in vivo and in vitro, suggesting that efficacy is highly dependent on inhibitor stereochemistry. 3 scyllo-Inositolinduced changes to the peptide assembly of Aβ(1-42) are very sensitive to structural perturbations of scyllo-inositol such as the number and orientation of the hydroxyl groups. 2 These structure− function studies revealed that even the most conservative single hydroxyl substitution led to a decrease in compound potency with only 1-deoxy-1-fluoro-scyllo-inositol retaining properties similar to the parent scyllo-inositol. 4
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