Dysfunctional interactions of metal ions, especially Cu, Zn, and Fe, with the amyloid-
![](/images/gifchars/beta2.gif)
(A
![](/images/gifchars/beta2.gif)
) peptideare hypothesized to play an important role in the etiology of Alzheimer's disease (AD). In addition to directeffects on A
![](/images/gifchars/beta2.gif)
aggregation, both Cu and Fe catalyze the generation of reactive oxygen species (ROS) inthe brain further contributing to neurodegeneration. Disruption of these aberrant metal-peptide interactionsvia chelation therapy holds considerable promise as a therapeutic strategy to combat this presently incurabledisease. To this end, we developed two multifunctional carbohydrate-containing compounds
N,
N'-bis[(5-
![](/images/gifchars/beta2.gif)
-
D-glucopyranosyloxy-2-hydroxy)benzyl]-
N,
N'-dimethyl-ethane-1,2-diamine (
H2GL1) and
N,
N'-bis[(5-
![](/images/gifchars/beta2.gif)
-
D-glucopyranosyloxy-3-
tert-butyl-2-hydroxy)benzyl]-
N,
N'-dimethyl-ethane-1,2-diamine (
H2GL2) for brain-directed metal chelation and redistribution. Acidity constants were determined by potentiometry aided byUV-vis and
1H NMR measurements to identify the protonation sites of
H2GL1,2. Intramolecular H bondingbetween the amine nitrogen atoms and the H atoms of the hydroxyl groups was determined to have animportant stabilizing effect in solution for the
H2GL1 and
H2GL2 species. Both
H2GL1 and
H2GL2 were foundto have significant antioxidant capacity on the basis of an in vitro antioxidant assay. The neutral metalcomplexes
CuGL1,
NiGL1,
CuGL2, and
NiGL2 were synthesized and fully characterized. A square-planararrangement of the tetradentate ligand around
CuGL2 and
NiGL2 was determined by X-ray crystallographywith the sugar moieties remaining pendant. The coordination properties of
H2GL1,2 were also investigatedby potentiometry, and as expected, both ligands displayed a higher affinity for Cu
2+ over Zn
2+ with
H2GL1displaying better coordinating ability at physiological pH. Both
H2GL1 and
H2GL2 were found to reduceZn
2+- and Cu
2+- induced A
1-40 aggregation in vitro, further demonstrating the potential of thesemultifunctional agents as AD therapeutics.