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Cited by 141Alzheimer's disease research and treatmentsCholinesterase and Neurodegenerative DiseasesDementia and Cognitive Impairment Research

Preliminary studies of a novel bifunctional metal chelator targeting Alzheimer's amyloidogenesis

Dedeoglu, Alpaslan, Cormier, Kerry, Payton, Sandra, Tseitlin, Katya A., Kremsky, Jonathan N., Lai, Li, Li, Xiaohua, Moir, Robert D. +5 more·2004·Experimental Gerontology
DOI 10.1016/j.exger.2004.08.016
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Abstract

A growing body of evidence indicates that dysregulation of cerebral biometals (Fe, Cu, Zn) and their interactions with APP and Abeta amyloid may contribute to the Alzheimer's amyloid pathology, and thus metal chelation could be a rational therapeutic approach for interdicting AD pathogenesis. However, poor target specificity and consequential clinical safety of current metal-complexing agents have limited their widespread clinical use. To develop the next generation of metal chelators, we have designed and synthesized a new bifunctional molecule-XH1, based on a novel 'pharmacophore conjugation' concept. This lipophilic molecule has both amyloid-binding and metal-chelating moieties covalently connected by amide bonds. It achieved a putative binding geometry with Abeta1-40 peptide by the computational chemistry modeling and reduced Zn(II)-induced Abeta1-40 aggregation in vitro as determined by turbidometry. Moreover, our pilot data indicated that XH1 has no significant neurotoxicity at low micromolar concentrations and acute animal toxicity. XH1 specifically reduced APP protein expression in human SH-SY5Y neuroblastoma cells and attenuated cerebral Abeta amyloid pathology in PS1/APP transgenic mice without inducing apparent toxicity and behavior disturbances. Collectively, these preliminary findings carry implication for XH1 being a BBB-permeable lead compound for AD therapeutics targeting Alzheimer's amyloidogenesis, although further studies are needed.

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  • Two approaches have been pursued in BFC design: direct incorporation of metal-binding atom donors into the structural framework of an Aβ-interacting compound, and linking the metal-chelating and Aβ-binding molecular fragments.

    “In this context, two approaches have been pursued in BFC design. 31,49–58 One strategy is based on the direct incorporation of metal-binding atom donors into the structural framework of an Aβ-interacting compoud (Scheme 1, approach A), and the other involves linking the metal-chelating and Aβ-binding molecular fragments (Scheme 1, approach B).”

    From Bifunctional Compounds for Controlling Metal-Mediated Aggregation of the Aβ<sub>42</sub>Peptide (2012) · cites this paper as [54]

  • Other reported BFCs have employed benzothiazole fragments as amyloid-binding motifs, but no binding affinities for the Aβ species have been measured for those systems.

    “While other reported BFCs have employed benzothiazole fragments as amyloid-binding motifs, no binding affinities for the Aβ species have been measured for those systems.49,53,54”

    From Bifunctional Compounds for Controlling Metal-Mediated Aggregation of the Aβ<sub>42</sub>Peptide (2012) · cites this paper as [54]

  • Recent efforts to control abnormal Aβ-metal interactions have focused on small molecules, bifunctional chelators (BFCs), that have binding affinity for both metal ions and Aβ aggregates.

    “Recent efforts to control abnormal Aβ–metal interactions have focused on small molecules, bifunctional chelators (BFCs), that have binding affinity for both metal ions and Aβ aggregates.20,25,27−30”

    From Small Bifunctional Chelators That Do Not Disaggregate Amyloid β Fibrils Exhibit Reduced Cellular Toxicity (2014) · cites this paper as [27]

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Authors
Dedeoglu, A., Cormier, K., Payton, S., Tseitlin, K. A., Kremsky, J. N., Lai, L., Li, X., Moir, R. D., Tanzi, R. E., Bush, A. I., Kowall, N. W., Rogers, J. T., & Huang, X.
Affiliations
  • Boston University (US)
  • Harvard University (US)
Corresponding author
Huang, Xudong
ORCID
Venue
Experimental Gerontology
Publisher
Elsevier BV
Published
2004-11
Volume
39
Issue
11-12
Pages
1641-1649
ISSN
0531-5565 (ISSN-L)
DOI
10.1016/j.exger.2004.08.016
OpenAlex
W2041230020
Cited by
141
References
42
Citations by year
2024: 5 · 2023: 5 · 2022: 1 · 2021: 9 · 2020: 7 · 2019: 4 · 2018: 3 · 2017: 5 · 2015: 4 · 2014: 9 · 2013: 5 · 2012: 11
FWCI
4.33
Type
journal article
Language
en
Open access
closed
Licence
Locations
  • Experimental Gerontology (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • American Foundation for Aging Research
  • National Institutes of Health (5K01MH02001)
  • Alzheimer's Association (NIRG 023563, AG13846, AG21081)
  • U.S. Department of Veterans Affairs
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Health Sciences › Medicine › Pharmacology › Cholinesterase and Neurodegenerative Diseases
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
Keywords
Alzheimer's disease, amyloidogenesis, amyloid-beta, metal chelators, zinc chelation, bifunctional molecules, amyloid binding, APP expression, amyloid fibril formation, blood-brain barrier permeability, neurotoxicity, lead compounds
MeSH terms
Aged, Alzheimer Disease, Amyloidosis, Animals, Brain, Brain Chemistry, Brain Neoplasms, Chelating Agents, Female, Humans, Immunohistochemistry, Metals, Mice, Transgenic, Neuroblastoma, Peptide Fragments, Amyloid beta-Peptides, Amyloid beta-Protein Precursor, Cell Line, Tumor, Mice

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