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

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...

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Autores principales: Porter, Meghan R., Kochi, Akiko, Karty, Jonathan A., Lim, Mi Hee, Zaleski, Jeffrey M.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Royal Society of Chemistry 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5811126/
https://www.ncbi.nlm.nih.gov/pubmed/29560189
http://dx.doi.org/10.1039/c4sc01979b
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author Porter, Meghan R.
Kochi, Akiko
Karty, Jonathan A.
Lim, Mi Hee
Zaleski, Jeffrey M.
author_facet Porter, Meghan R.
Kochi, Akiko
Karty, Jonathan A.
Lim, Mi Hee
Zaleski, Jeffrey M.
author_sort Porter, Meghan R.
collection PubMed
description 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 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)–Aβ species. In the presence of Aβ(40/42) 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 CO(2) 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.
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spelling pubmed-58111262018-03-20 Chelation-induced diradical formation as an approach to modulation of the amyloid-β aggregation pathway Porter, Meghan R. Kochi, Akiko Karty, Jonathan A. Lim, Mi Hee Zaleski, Jeffrey M. Chem Sci Chemistry 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 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)–Aβ species. In the presence of Aβ(40/42) 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 CO(2) 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. Royal Society of Chemistry 2015-02-01 2014-10-30 /pmc/articles/PMC5811126/ /pubmed/29560189 http://dx.doi.org/10.1039/c4sc01979b Text en This journal is © The Royal Society of Chemistry 2014 http://creativecommons.org/licenses/by/3.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution 3.0 Unported License (http://creativecommons.org/licenses/by/3.0/) which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Chemistry
Porter, Meghan R.
Kochi, Akiko
Karty, Jonathan A.
Lim, Mi Hee
Zaleski, Jeffrey M.
Chelation-induced diradical formation as an approach to modulation of the amyloid-β aggregation pathway
title Chelation-induced diradical formation as an approach to modulation of the amyloid-β aggregation pathway
title_full Chelation-induced diradical formation as an approach to modulation of the amyloid-β aggregation pathway
title_fullStr Chelation-induced diradical formation as an approach to modulation of the amyloid-β aggregation pathway
title_full_unstemmed Chelation-induced diradical formation as an approach to modulation of the amyloid-β aggregation pathway
title_short Chelation-induced diradical formation as an approach to modulation of the amyloid-β aggregation pathway
title_sort chelation-induced diradical formation as an approach to modulation of the amyloid-β aggregation pathway
topic Chemistry
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5811126/
https://www.ncbi.nlm.nih.gov/pubmed/29560189
http://dx.doi.org/10.1039/c4sc01979b
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