Journal
JOURNAL OF INORGANIC BIOCHEMISTRY
Volume 158, Issue -, Pages 131-138Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.jinorgbio.2016.04.022
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Metal ion dyshomeostasis is hypothesized to play a role in the toxicity and aggregation of the amyloid beta (A beta) peptide, contributing to Alzheimer's disease (AD) pathology. We report on the synthesis and metal complexation ability of three bidentate quinoline-triazole derivatives 3-(4-(quinolin-2-yl)-1H-1,2,3-triazol-1-yl)propan-1-ol (QOH), 4-(2-(4-(quinolin-2-yl)-1H-1,2,3-triazol-1-yl)ethyl)morpholine (QMorph), and 4-(2-(4-(quinolin-2-yl)-1H-1,2,3-triazol-1-yl)ethyl)thiomorpholine (QTMorph). We further study the utility of these ligands to modulate A beta peptide aggregation processes in the presence and absence of Cu2+ ions. Ligand-peptide interactions were first investigated using both 2-D H-1-N-15 band-selective optimized flip angle short transient heteronuclear multiple quantum correlation (SOFAST-HMQC) NMR spectroscopy and molecular modeling techniques, indicating interactions with glutamic acid (E3) and several residues in the hydrophobic region of A beta. Native gel electrophoresis with western blotting along with transmission electron microscopy provided information on the ability of each ligand to modulate A beta aggregation. While the ligands alone did not modify A beta peptide aggregation at the 24 h timepoint, signifying relatively weak ligand-peptide interactions, the ligands did modify the aggregation profile of the peptide in the presence of stoichiometric and suprastoichiometric Cu. Interestingly, the thioether derivative QTMorph exhibited the most pronounced effect on peptide aggregation in the presence of Cu. Overall, the quinoline-triazole ligand series were shown to interact with the hydrophobic region of the A beta peptide, and modulate the Cu-A beta aggregation process. (c) 2016 Elsevier Inc. All rights reserved.
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