Issue 2, 2015

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

Abstract

Current approaches toward modulation of metal-induced Aβ aggregation pathways involve the development of small molecules that bind metal ions, such as Cu(II) and Zn(II), and interact with Aβ. 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 Bergman-cyclization to yield diradical formation. The ability of this chelation-triggered diradical to modulate Aβ 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 pKa = 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 Kd, suggesting the ligand may be capable of interacting with Cu(II)–Aβ species. In the presence of Aβ40/42 under hyperthermic conditions (43 °C), the radical-generating PyED demonstrates markedly enhanced activity (2–24 h) toward the modulation of Aβ 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)–Aβ cases. The loss of CO2 from the metal binding region of Aβ in MALDI-TOF mass spectra further suggests that metal–ligand–Aβ interaction with subsequent radical formation may play a role in the aggregation pathway modulation.

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

Supplementary files

Article information

Article type
Edge Article
Submitted
02 Jul 2014
Accepted
30 Oct 2014
First published
30 Oct 2014
This article is Open Access

All publication charges for this article have been paid for by the Royal Society of Chemistry
Creative Commons BY license

Chem. Sci., 2015,6, 1018-1026

Author version available

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

M. R. Porter, A. Kochi, J. A. Karty, M. H. Lim and J. M. Zaleski, Chem. Sci., 2015, 6, 1018 DOI: 10.1039/C4SC01979B

This article is licensed under a Creative Commons Attribution 3.0 Unported Licence. You can use material from this article in other publications without requesting further permissions from the RSC, provided that the correct acknowledgement is given.

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