Glycosylated tetrahydrosalens as multifunctional molecules for Alzheimer's therapy

• Published in: Dalton transactions : an international journal of inorganic chemistry no. 16; p. 3034
• Main Authors: Storr, Tim, Scott, Lauren E, Bowen, Meryn L, Green, David E, Thompson, Katherine H, Schugar, Harvey J, Orvig, Chris
• Format: Journal Article
• Language: English
• Published: England 01-01-2009
• Subjects: Alzheimer Disease - drug therapy; Amyloid beta-Peptides - metabolism; Antioxidants - chemistry; Cell Line, Tumor; Cell Survival - drug effects; Chromans - chemistry; Ethylenediamines - chemical synthesis; Ethylenediamines - chemistry; Ethylenediamines - metabolism; Ethylenediamines - toxicity; Glycosylation; Humans; Ligands; Molecular Structure; Peptide Fragments - metabolism
• ISSN: 1477-9226
• DOI: 10.1039/b902545f

The tetrahydrosalens N,N'-bis(2-hydroxybenzyl)-ethane-1,2-diamine ((2)(1)), N,N'-bis(2-hydroxybenzyl)-(-)-1,2-cyclohexane-(1R,2R)-diamine ((2)(2)), N,N'-bis(2-hydroxybenzyl)-N,N'-dimethyl-ethane-1,2-diamine ((2)(3)), N,N'-bis(2-hydroxybenzyl)-N,N'-dibenzyl-ethane-1,2-diamine ((2)(4)), and N,N'-bis(2-(4-tert-butyl)hydroxybenzyl)-ethane-1,2-diamine ((2)(5)), as well as their prodrug glycosylated forms, (1-5), have been prepared and evaluated in vitro for their potential use as Alzheimer's disease (AD) therapeutics. Dysfunctional interactions of metal ions, especially those of Cu, Zn, and Fe, with the amyloid-beta (Abeta) peptide are hypothesised to play an important role in the aetiology of AD, and disruption of these aberrant metal-peptide interactions via chelation therapy holds considerable promise as a therapeutic strategy. Tetrahydrosalens such as (2)(1-5) have a significant affinity for metal ions, and thus should be able to compete with the Abeta peptide for Cu, Zn, and Fe in the brain. This activity was assayed in vitrovia a turbidity assay; (2)(1) and (2)(3) were found to attenuate Abeta(1-40) aggregation after exposure to Cu(2+) and Zn(2+). In addition, (2)(1-5) were determined to be potent antioxidants on the basis of an in vitro antioxidant assay. (1-5) were prepared as metal binding prodrugs; glycosylation is intended to prevent systemic metal binding, improve solubility, and enhance brain uptake. Enzymatic (beta-glucosidase) deprotection of the carbohydrate moieties was facile, with the exception of (4), demonstrating the general feasibility of this prodrug approach. Finally, a representative prodrug, (3), was determined to be non-toxic over a large concentration range in a cell viability assay.