Functionalised Azamacrocycles for Modulating Amyloid Aggregation

Abstract

Alzheimer’s disease (AD) is a common, fatal polygenic neurodegenerative disorder, which still lacks satisfactory therapy or a preventative treatment. Among various hypotheses, the amyloid β (Aβ) cascade hypothesis is a widely accepted explanation by which Aβ aggregation is the causative process in AD pathology. Controlling this aggregation and understanding the structure of the resulting aggregates are core challenges to further understanding of AD. New, bioavailable small-molecule probes with programmable geometries, designed to interact with Aβ, have been obtained in high yields. These probes include functionalized azamacrocycles cyclam and cyclen, connected to pendants through triazole linkers that can coordinate to a central metal ion. It has been shown that probes with different structures have different abilities to influence Aβ aggregation, and therefore potentially capacity to protect neurons from Aβ toxicity by diverting the aggregation behavior of Aβ to alternative endpoints. The aim of this project is to synthesize new functionalized azamacrocycles, which can interact with Aβ and redirect aggregation pathways. A series of tetra-N-substituted cyclam compounds with various pendant groups and triazole group as the linker have been synthesized and characterized. The synthetic approach involves a nucleophilic substitution reaction, copper-catalyzed azide-alkyne cycloaddition (CuAAC) reactions, bromination, tetra-N-alkylation, protonation and metal complexation. Thioflavin T (ThT) fluorescence assays and small angle X-ray scattering (SAXS) experiments were conducted with the novel compounds on Aβ40/42 peptides and other amyloidogenic hydrophobins, the results of which will be discussed in terms of protein binding, surface tension modification, and fluorescence quenching