Synthesis, characterization, and metal coordinating ability of multifunctional carbohydrate-containing compounds for Alzheimer's therapy

Dysfunctional interactions of metal ions, especially Cu, Zn, and Fe, with the amyloid-beta (A beta) peptide are hypothesized to play an important role in the etiology of Alzheimer's disease (AD). In addition to direct effects on A, aggregation, both Cu and Fe catalyze the generation of reactive oxygen species (ROS) in the brain further contributing to neurodegeneration. Disruption of these aberrant metal-peptide interactions via chelation therapy holds considerable promise as a therapeutic strategy to combat this presently incurable disease. To this end, we developed two multifunctional carbohydrate-containing compounds N, N '-bis[(5- beta-D-glucopyranosyloxy-2-hydroxy) benzyl]-N, N '-dimethyl-ethane-1,2-diamine (H(2)GL(1)) and N, N '-bis[(5-beta-D-glucopyranosyloxy-3- tert-butyl-2-hydroxy) benzyl]-N,N '-dimethyl-ethane-1,2-diamine (H(2)GL(2)) for brain-directed metal chelation and redistribution. Acidity constants were determined by potentiometry aided by UV-vis and H-1 NMR measurements to identify the protonation sites of H(2)GL(1,2). Intramolecular H bonding between the amine nitrogen atoms and the H atoms of the hydroxyl groups was determined to have an important stabilizing effect in solution for the H(2)GL(1) and H(2)GL(2) species. Both H(2)GL(1) and H(2)GL(2) were found to have significant antioxidant capacity on the basis of an in vitro antioxidant assay. The neutral metal complexes CuGL(1), NiGL(1), CuGL(2), and NiGL(2) were synthesized and fully characterized. A square-planar arrangement of the tetradentate ligand around CuGL(2) and NiGL(2) was determined by X-ray crystallography with the sugar moieties remaining pendant. The coordination properties of H(2)GL(1,2) were also investigated by potentiometry, and as expected, both ligands displayed a higher affinity for Cu2+ over Zn2+ with H(2)GL(1) displaying better coordinating ability at physiological pH. Both H(2)GL(1) and H(2)GL(2) were found to reduce Zn2+-and Cu2+-induced A beta(1-40) aggregation in vitro, further demonstrating the potential of these multifunctional agents as AD therapeutics.