Multifunctional quinoline-triazole derivatives as potential modulators of amyloid-β peptide aggregation

Abstract

Metal ion dyshomeostasis is hypothesized to play a role in the toxicity and aggregation of the amyloid beta (Aβ) 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 Aβ peptide aggregation processes in the presence and absence of Cu 2+ ions. Ligand-peptide interactions were first investigated using both 2-D 1 H-15 N SOFAST-HMQC NMR spectroscopy and molecular modeling techniques, indicating interactions with E3 and several residues in the hydrophobic region of Aβ. Native gel electrophoresis with western blotting along with transmission electron microscopy provided information on the ability of each ligand to modulate Aβ aggregation. While the ligands alone did not modify Aβ peptide aggregation at the 24 hour 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 Aβ peptide, and modulate Cu-Aβ aggregation process.

Self-assembling peptide-based building blocks in medical applications

“…Protein aggregation and amyloid formation has become the subject of rapidly increasing interdisciplinary research activities, in order to understand and control the triggering factors of aggregation. The native form of Aβ is unfolded but can aggregate into fibrillar structures under various conditions and environmental manipulations, such as solvents [113], inorganic elements [114], or nanoparticles [115]. The key motif of Aβ peptides induces cellular membrane disruption, which has made it a potential target for pharmacological inventions recently [116–118].…”

A small bifunctional chelator that modulates Aβ42 aggregation

“…Click chemistry can be used effectively to connect various functional entities through a copper-catalyzed Huisgentype 1,3-dipolar cycloaddition of terminal alkynes and organic azides. A series of dual-function triazole-pyridine ligands 16 and multifunctional quinoline-triazole ligands 17 have been previously reported by our group (Fig. 1).…”

“…1. [16][17][18][19][20][21] A␤ is derived from the proteolytic cleavage of APP by ␤and ␥-secretases. 22 The aggregation of A␤ leads to the formation of senile plaques (SP), which is one of the hallmarks of AD brains, 2 where the plaques cause neuronal destruction and are associated with oxidative stress, mitochondrial dysfunction, loss of membrane integrity, abnormal calcium homeostasis, and induced apoptosis.…”

“…16 The quinoline-triazole series weakly interact with the A␤ peptide and only modify the aggregation profile of the A␤ peptide in the presence of excess Cu ions (1.4:1). 17 In this paper, we focused on the design of a multifunctional ligand with increased peptide interactions and a higher affinity for Cu. In structure-reactivity investigations of multifunctional ligands in both the absence and presence of metal ions for their antiamyloidogenic characteristics, it was evident that the dimethylamino group is a key component for the activity of the ligand.…”

“…In structure-reactivity investigations of multifunctional ligands in both the absence and presence of metal ions for their antiamyloidogenic characteristics, it was evident that the dimethylamino group is a key component for the activity of the ligand. 28,29 Based on a structure-mechanism design strategy 18 and the previous work, 16,17,28,29 a novel triazole-phenol derivative was designed (Scheme 1) inspired by the metal chelator clioquinol (CQ) and a known A␤ imaging agent, a p-I-stilbene derivative. 30 The metal-binding properties of the new ligand, its interaction with A␤, and its potential blood-brain barrier (BBB) permeability were evaluated.…”