BROWSE

Related Researcher

Author's Photo

Lim, Mi Hee
MetalloNeuroChemistry Lab (MNCL)
Research Interests
  • Neurodegenerative disease, small molecule design, network between metal, proteins, and ROS

ITEM VIEW & DOWNLOAD

Chelation-induced diradical formation as an approach to modulation of the amyloid-β aggregation pathway

Cited 1 times inthomson ciCited 0 times inthomson ci
Title
Chelation-induced diradical formation as an approach to modulation of the amyloid-β aggregation pathway
Author
Porter, Meghan R.Kochi, AkikoKarty, Jonathan A.Lim, Mi HeeZaleski, Jeffrey M.
Issue Date
2015-02
Publisher
ROYAL SOC CHEMISTRY
Citation
CHEMICAL SCIENCE, v.6, no.2, pp.1018 - 1026
Abstract
Current approaches toward modulation of metal-induced A beta aggregation pathways involve the development of small molecules that bind metal ions, such as Cu(II) and Zn(II), and interact with Ab. For this effort, we present the enediyne-containing ligand (Z)-N, N'-bis[1-pyridin-2-yl-meth(E)-ylidene]oct-4-ene- 2,6-diyne-1,8-diamine (PyED), which upon chelation of Cu(II) and Zn(II) undergoes Bergmancyclization to yield diradical formation. The ability of this chelation-triggered diradical to modulate Ab aggregation is evaluated relative to the non-radical generating control pyridine-2-ylmethyl(2-{[(pyridine-2-ylmethylene)-amino]-methyl}-benzyl)-amine (PyBD). Variable-pH, ligand UV-vis titrations reveal pK(a) = 3.81(2) for PyBD, indicating it exists mainly in the neutral form at experimental pH. Lipinski's rule parameters and evaluation of blood-brain barrier (BBB) penetration potential by the PAMPA-BBB assay suggest that PyED may be CNS+ and penetrate the BBB. Both PyED and PyBD bind Zn(II) and Cu(II) as illustrated by bathochromic shifts of their UV-vis features. Speciation diagrams indicate that Cu(II)PyBD is the major species at pH 6.6 with a nanomolar K-d, suggesting the ligand may be capable of interacting with Cu(II)-A beta species. In the presence of A beta(40/42) under hyperthermic conditions (43 degrees C), the radical-generating PyED demonstrates markedly enhanced activity (2-24 h) toward the modulation of A beta species as determined by gel electrophoresis. Correspondingly, transmission electron microscopy images of these samples show distinct morphological changes to the fibril structure that are most prominent for Cu(II)-A beta cases. The loss of CO2 from the metal binding region of A beta in MALDI-TOF mass spectra further suggests that metal-ligand-A beta interaction with subsequent radical formation may play a role in the aggregation pathway modulation.
URI
https://scholarworks.unist.ac.kr/handle/201301/10744
URL
http://pubs.rsc.org/en/Content/ArticleLanding/2015/SC/C4SC01979B#!divAbstract
DOI
10.1039/c4sc01979b
ISSN
2041-6520
Appears in Collections:
PHY_Journal Papers
Files in This Item:
c4sc01979b.pdf Download

find_unist can give you direct access to the published full text of this article. (UNISTARs only)

Show full item record

qrcode

  • mendeley

    citeulike

Items in DSpace are protected by copyright, with all rights reserved, unless otherwise indicated.

MENU