scyllo-Inositol is currently in phase II clinical trials as a therapeutic for Alzheimer’s disease (AD). Previous work from our lab has shown that scyllo-inositol prevents Ab1-42 fibril formation instead leading to the formation of small Ab oligomers in vitro. To further understand the molecular details of Ab-scyllo-inositol binding interactions, a library of scyllo-inositol derivatives was prepared. A sequence of protecting group transformations afforded a hydroxylamine functionalized scyllo-inositol. Subsequent oxime formation with aromatic aldehydes generated a novel class of inositol derivatives in good yield and high purity. The effects of these compounds on the Ab aggregation cascade were evaluated by a biotin-avidin Ab1-42 oligomer assay and atomic force microscopy (AFM). Preliminary plate assay data indicated that several of these derivatives increased peptide oligomerization and the corresponding AFM images showed altered fibril formation. These results suggested that this class of scyllo-inositol derivatives is active in the Ab aggregation cascade.
| Identifer | oai:union.ndltd.org:TORONTO/oai:tspace.library.utoronto.ca:1807/24951 |
| Date | 11 October 2010 |
| Creators | Chio, Song Ngai |
| Contributors | Nitz, Mark |
| Source Sets | University of Toronto |
| Language | en_ca |
| Detected Language | English |
| Type | Thesis |
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