Reactivities of cyclam derivatives with metal-amyloid-beta

Abstract

Amyloid-beta (A beta) aggregation and metal ion dyshomeostasis are found to be pathological features upon the progress of Alzheimer's disease (AD). In addition, A beta and metal ions are reported to interact with each other forming metal-A beta complexes, which can affect the aggregation of A beta and cause oxidative stress via the production of reactive oxygen species (ROS). To disrupt metal coordination to A beta and control the reactivities of metal-A beta, metal chelating agents have been tested. Herein, a series of azamacrocyclic compounds with different properties of Cu(ii) and Zn(ii) binding and A beta 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-A beta and the generation of ROS mediated by metal-A beta were evaluated. Their modulative reactivities towards metal-A beta could be achieved by generating a ternary complex with metal-A beta and chelating the metal ion from metal-A beta. Moreover, the toxicity induced by metal-A beta in living cells was alleviated by the cyclam derivatives capable of regulating metal-A beta aggregation and metal-A beta-triggered ROS formation. Overall, our studies illustrate new examples of azamacrocyclic metal chelators that alter the interactions between metal ions and A beta and subsequently modify the reactivities of metal-A beta, with an indication of how the slight structure-property difference can influence such effects of small molecules.