Glycosylated tetrahydrosalens as multifunctional molecules for Alzheimer's therapy.
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.
Storr
Tim
T
Medicinal Inorganic Chemistry Group, Department of Chemistry, University of British Columbia, 2036 Main Mall, Vancouver, British Columbia, V6T 1Z1, Canada.
Scott
Lauren E
LE
Bowen
Meryn L
ML
Green
David E
DE
Thompson
Katherine H
KH
Schugar
Harvey J
HJ
Orvig
Chris
C
D000544:Alzheimer Disease / Q000188:drug therapy*; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000975:Antioxidants / Q000737:chemistry; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002839:Chromans / Q000737:chemistry; D005029:Ethylenediamines / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism / Q000633:toxicity; D006031:Glycosylation; D006801:Humans; D008024:Ligands; D015394:Molecular Structure; D010446:Peptide Fragments / Q000378:metabolism
D016229:Amyloid beta-Peptides; D000975:Antioxidants; D002839:Chromans; D005029:Ethylenediamines; D008024:Ligands; D010446:Peptide Fragments; C011452:disalicylaldehyde ethylenediamine; C010643:6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid