Synthesis, Characterization, and Metal Coordinating Ability of Multifunctional Carbohydrate-Containing Compounds for Alzheimer's Therapy

Abstract

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 beta 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 (H2GL1) and N,N'-bis[(5-beta-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 by UV-vis and 1H NMR measurements to identify the protonation sites of H2GL1,2. 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 H2GL1 and H2GL2 species. Both H2GL1 and H2GL2 were found to have significant antioxidant capacity on the basis of an in vitro antioxidant assay. The neutral metal complexes CuGL1, NiGL1, CuGL2, and NiGL2 were synthesized and fully characterized. A square-planar arrangement of the tetradentate ligand around CuGL2 and NiGL2 was determined by X-ray crystallography with the sugar moieties remaining pendant. The coordination properties of H2GL1,2 were also investigated by potentiometry, and as expected, both ligands displayed a higher affinity for Cu2+ over Zn2+ with H2GL1 displaying better coordinating ability at physiological pH. Both H2GL1 and H2GL2 were found to reduce Zn2+- and Cu2+- induced Abeta1-40 aggregation in vitro, further demonstrating the potential of these multifunctional agents as AD therapeutics.

Design of small molecules that target metal-Aβ species and regulate metal-induced Aβ aggregation and neurotoxicity

“…From these solution speciation diagrams, the concentrations of unchelated Cu 2þ and Zn 2þ (pM ¼ − log½M unchelated ) at a specific pH value can be calculated (pCu ¼ 9.9 and 10.2 at pH 6.6 and pH 7.4, respectively; pZn ¼ 6.1 at pH 7.4). The pM values represent the metal binding affinity of L2-b at a specific pH value as well as an estimate of its ability to sequester metal ions bound to Aβ peptide (21,35). The pCu and pZn values for L2-b, corresponding to approximate dissociation constants (K d ), indicated that these K d values were comparable to the reported ones of Cu-Aβ (picomolar to nanomolar) and Zn-Aβ (micromolar) (2,3,8,9,21,(35)(36)(37).…”

“…The pM values represent the metal binding affinity of L2-b at a specific pH value as well as an estimate of its ability to sequester metal ions bound to Aβ peptide (21,35). The pCu and pZn values for L2-b, corresponding to approximate dissociation constants (K d ), indicated that these K d values were comparable to the reported ones of Cu-Aβ (picomolar to nanomolar) and Zn-Aβ (micromolar) (2,3,8,9,21,(35)(36)(37). Thus, the affinities of L2-b for Cu 2þ and Zn 2þ at the relevant pHs [for metal-induced Aβ aggregation (2-4, 7-9)] suggest that this compound is able to chelate metal ions from soluble Aβ species, which could support the results from reactivity studies of L2-b with metal-treated Aβ species (vide infra).…”

Supramolecular Assembly of Carbohydrate‐Functionalized Salphen–Metal Complexes

“…[14] Orvig and co-workers have investigated salen-based ligands with glucose attached as metal-chelating agents for treating Alzheimers disease. [15] We have been interested in the supramolecular assembly of Schiff base macrocycles based on salphen. [16,17] With the notion that hydrogen bonding between monosaccharidesplexes or macrocycles, we set out to prepare new Schiff base complexes with appended glucosyl or galactosyl groups.…”

8-Hydroxyquinoline Schiff-base compounds as antioxidants and modulators of copper-mediated Aβ peptide aggregation

“…48,70,90 The ability of the compounds to quench the 403 ABTS˙+ radical cation was compared to Trolox, a water-soluble analog of ±--404 tocopherol (Fig. 6) Insert Fig.7 436 …”