Synthesis of scyllo-inositol derivatives and their effects on amyloid beta peptide aggregation

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Abstract

scyllo-Inositol has shown promise as a potential therapeutic for Alzheimer’s disease, by directly interacting with the amyloid β (Aβ) peptide to inhibit Aβ42 fiber formation. To explore the molecular details of the inositol-Aβ42 interaction, a series of scyllo-inositol derivatives have been synthesized which contain deoxy, fluoro, chloro, and methoxy substitutions. The effects of these compounds on the aggregation cascade of Aβ42 have been investigated using electron microscopy (EM). EM analyses revealed that the 1-deoxy-1-fluoro- and 1,4-dimethyl-scyllo-inositols significantly inhibit the formation of Aβ42 fibers. The other derivatives showed some alterations in the morphology of the Aβ42 fibers produced. These findings indicate the importance of all of the hydroxyl groups of scyllo-inositol for complete inhibition of aggregation.

Introduction

Alzheimer’s disease (AD), the most common cause of dementia in individuals over the age of 65, is a progressive neurodegenerative disorder characterized clinically by cognitive impairment and memory loss.1 Many research groups have sought to design compounds which inhibit or disrupt Aβ peptide aggregation as a therapeutic strategy to treat AD.2 These compounds have a range of structures including a large number of polyphenols, peptides, tetracyclines, copper, and zinc chelators as well as many aromatic heterocycles.3, 4, 5, 6, 7, 8

Previous work from our laboratory has demonstrated that scyllo-inositol is able to directly interact with the Aβ42 peptide, the most neurotoxic component of the senile plaques that are deposited in Alzheimer’s disease (AD).9, 10, 11 Results from in vitro experiments have shown that incubation of randomly structured Aβ42 with scyllo-inositol induced an immediate change in the secondary structure of the peptide, stabilized small Aβ oligomers and completely blocked fibril formation.10 Oral administration of scyllo-inositol in the TgCRND8 mouse model of AD, inhibited Aβ aggregation, attenuated Aβ-induced impairments in spatial memory, reduced the cerebral Aβ pathology, and decreased the rate of mortality.12 These therapeutic effects occurred regardless of whether the compound was given before or well after the onset of the AD-like phenotype, suggesting that scyllo-inositol acts to both prevent plaque formation and disrupt pre-formed Aβ fibers.12

To date, the molecular details of the inositol binding site within the Aβ42 peptide remain unknown. Of the 12 stereochemically related inositols and inososes explored for their ability to inhibit Aβ42 fiber formation and Aβ42 cellular toxicity, scyllo-inositol remains the most potent compound.10, 11 Given the promise of scyllo-inositol as a potential therapeutic agent, and the specificity of the Aβ-scyllo-inositol interaction, we set out to explore the Aβ42-scyllo-inositol structure–function relationship by studying the effect of closely related scyllo-inositol derivatives on Aβ42 fiber formation. A series of scyllo-inositol derivatives were synthesized in which one or two of the hydroxyl groups were replaced with fluoro, chloro, methoxy or hydrogen substituents (Fig. 1). The approach of replacing hydroxyl groups on carbohydrate ligands with these substituents has provided information about hydrogen bonding requirements, hydrophobicity, and steric interactions of a given hydroxyl group in the carbohydrate binding site of lectins and antibodies.13, 14, 15 In this initial study, the effects of each scyllo-inositol derivative on Aβ42 aggregation were assessed by electron microscopy (EM). We report here that while all modifications alter the scyllo-inostiol-Aβ42 interaction, a single fluoro substitution, and the 1,4-dimethylation, of scyllo-inositol provides compounds which remain effective in preventing Aβ42 fiber formation.

Section snippets

Synthesis of scyllo-inositol derivatives

myo-Inositol was used as the starting material for the synthesis of all of the scyllo-inositol derivatives 18 (Fig. 1). The key bisacetal protected diol 9 was synthesized from myo-inositol using the previously reported condensation with 2,3-butanedione.16, 17 This persistent protecting group strategy allowed rapid access to the inositol derivatives 18. Selective benzoylation of the equatorial alcohol of diol 9 gave the protected alcohol 10 in 64% yield. Orthogonal to functionalization of the

Discussion

The synthesis of compounds 1,21 2,22 3,23 5,24 and 725 have been described previously by alternate synthetic routes. We developed the streamlined synthesis reported here to give the most direct route to a wide range of scyllo-inositol analogues including compounds 18 desired for our on-going investigations of the interaction between inositols and Aβ42.

We have previously demonstrated, and replicated in this report, that incubation of scyllo-inositol with randomly structured Aβ42 peptides

Conclusions

In conclusion, these studies provide a practical synthetic route to a series of scyllo-inositol derivatives. The preliminary data on the effects of these compounds on Aβ aggregation suggest that only the most conservative single hydroxyl substitutions are tolerated, thus 1-deoxy-1-fluoro-scyllo-inositol behaves similarly to the parent compound. But, the introduction of two hydrophobic substituents as in 1,4-dimethyl-scyllo-inostiol (8) also provides a potent compound for altering the Aβ42

Generalities for organic synthesis

Proton nuclear magnetic resonance spectra (1H NMR) and carbon nuclear magnetic resonance spectra (13C NMR) were recorded on a Varian Mercury 400 or Varian Mercury 300 NMR spectrometers. Chemical shifts for protons are reported in parts per million (δ scale) downfield from tetramethylsilane and are referenced to residual protium in the NMR solvents (CHCl3: δ 7.27, CD2HOD: δ 3.31). Chemical shifts for carbon resonances are reported in parts per million (δ scale) downfield from tetramethylsilane

Acknowledgments

The authors thank Dr. N.-C. Wang at the Hospital for Sick Children’s Biotechnology Center for synthesis of the Aβ42 peptide. The authors acknowledge support from the Canadian Institutes of Health Research (J.M., M.N., C.H., and G.Z,), Natural Science and Engineering Research Council of Canada (J.M., M.N., and G.Z.), Ontario Alzheimer’s Society (J.M.), and Alzheimer’s Society of Canada (C.H, J.E.S., and M.N.).

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