Reactivities of cyclam derivatives with metal–amyloid-β

Abstract

Amyloid-β (Aβ) aggregation and metal ion dyshomeostasis are found to be pathological features upon the progress of Alzheimer's disease (AD). In addition, Aβ and metal ions are reported to interact with each other forming metal–Aβ complexes, which can affect the aggregation of Aβ and cause oxidative stress via the production of reactive oxygen species (ROS). To disrupt metal coordination to Aβ and control the reactivities of metal–Aβ, metal chelating agents have been tested. Herein, a series of azamacrocyclic compounds with different properties of Cu(II) and Zn(II) binding and Aβ interaction were rationally selected under criteria based on structural and functional variations on the backbone of Cyclam. The series contains Cyclam, its N-methylated and cross-bridged (N-methylated or not) analogs, as well as their C-appended hydroxyethyl derivatives, and some of them have been newly synthesized. The reactivities of the cyclam derivatives towards the aggregation of metal–Aβ and the generation of ROS mediated by metal–Aβ were evaluated. Their modulative reactivities towards metal–Aβ could be achieved by generating a ternary complex with metal–Aβ and chelating the metal ion from metal–Aβ. Moreover, the toxicity induced by metal–Aβ in living cells was alleviated by the cyclam derivatives capable of regulating metal–Aβ aggregation and metal–Aβ-triggered ROS formation. Overall, our studies illustrate new examples of azamacrocyclic metal chelators that alter the interactions between metal ions and Aβ and subsequently modify the reactivities of metal–Aβ, with an indication of how the slight structure–property difference can influence such effects of small molecules.