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Cited by 159Alzheimer's disease research and treatmentsMetal complexes synthesis and propertiesMolecular Sensors and Ion Detection

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

Storr, Tim, Merkel, Michael, Song-Zhao, George X., Scott, Lauren E., Green, David E., Bowen, Meryn L., Thompson, Katherine H., Patrick, Brian O. +2 more·2007·Journal of the American Chemical Society
DOI 10.1021/ja068965r
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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 l…

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Crossref · 10.1021/ja068965r

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  • The two lower pKa values of L1 are assigned to deprotonation of the two pyridinium groups, the third to the ammonium group, and the highest to phenol deprotonation.

    “Based on previously reported acidity constants for phenols, amines,76 and pyridines,52 we assigned the two lower pKa values to the deprotonation of the two pyridinium groups, and the third pKa value to the ammonium group. The highest pKa value is likely due to phenol deprotonation in L1.”

    From Bifunctional Compounds for Controlling Metal-Mediated Aggregation of the Aβ<sub>42</sub>Peptide (2012) · cites this paper as [76]

  • The pM values compare favorably with Kd values reported for Cu-Aβ (nM-μM) and Zn-Aβ (μM).

    “These pM values represent approximate dissociation constants and compare favorably with the Kd values reported for Cu-Aβ (nM-μM) and Zn-Aβ (μM).26,29,31,57,76,79,80”

    From Bifunctional Compounds for Controlling Metal-Mediated Aggregation of the Aβ<sub>42</sub>Peptide (2012) · cites this paper as [76]

  • The first and second pKa values of L1 can be assigned to deprotonation of the nitrogen atoms of the benzothiazole and diethylamino groups, while the largest pKa value is likely due to phenol deprotonation.

    “The first and second pKa values can be assigned to deprotonation of the nitrogen atoms of the benzothiazole and diethylamino groups, while the largest pKa value is likely due to phenol deprotonation.25,42”

    From Small Bifunctional Chelators That Do Not Disaggregate Amyloid β Fibrils Exhibit Reduced Cellular Toxicity (2014) · cites this paper as [42]

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Authors
Storr, T., Merkel, M., Song-Zhao, G. X., Scott, L. E., Green, D. E., Bowen, M. L., Thompson, K. H., Patrick, B. O., Schugar, H. J., & Orvig, C.
Affiliations
Rutgers, The State University of New Jersey (US)
ORCID
Venue
Journal of the American Chemical Society
Publisher
American Chemical Society (ACS)
Published
2007-05-19
Volume
129
Issue
23
Pages
7453-7463
ISSN
  • 0002-7863 (ISSN-L)
  • 1520-5126
DOI
10.1021/ja068965r
OpenAlex
W1975829681
Cited by
156
References
118
Citations by year
2026: 3 · 2025: 3 · 2024: 5 · 2023: 10 · 2022: 2 · 2021: 9 · 2020: 7 · 2019: 6 · 2018: 7 · 2017: 10 · 2016: 7 · 2015: 9 · 2014: 10 · 2013: 10 · 2012: 13
FWCI
6.87
Type
journal article
Language
en
Open access
closed
Locations
  • Journal of the American Chemical Society (publishedVersion)
  • PubMed (publishedVersion)
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Health Sciences › Medicine › Oncology › Metal complexes synthesis and properties
  • Physical Sciences › Chemistry › Spectroscopy › Molecular Sensors and Ion Detection
Keywords
Alzheimer's disease, amyloid-beta aggregation, chelation therapy, copper complexes, zinc complexes, reactive oxygen species, antioxidant capacity, protonation sites, intramolecular hydrogen bonding, tetradentate ligands, square-planar coordination
MeSH terms
Alzheimer Disease, Antioxidants, Carbohydrates, Chelating Agents, Copper, Glucosides, Iron, Ligands, Potentiometry, Zinc, Drug Design, Molecular Structure, Crystallography, X-Ray, Metals, Heavy

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