Small Molecule Modulators of Copper-Induced Aβ Aggregation

Our design of bifunctional metal chelators as chemical probes and potential therapeutics for Alzheimer's disease (AD) is based on the incorporation of a metal binding moiety into structural frameworks of AB aggregate-imaging agents. Using this strategy, two compounds 2-[4-(dimethylamino)phenyl]imidazo[1,2-a]pyridine-8-ol (1) and N-1,N-1-dimethyl-N-4-(pyridin-2-ylmethylene)benzene-1,4-diamine (2) were prepared and characterized. The bifunctionality for metal chelation and AB interaction of 1 and 2 was verified by spectroscopic methods. Furthermore, the reactivity of 1 and 2 with Cu-II-associated AB aggregates was investigated. The modulation of Cu-II-triggered AB aggregation by 1 and 2 was found to be more effective than that by the known metal chelating agents CQ, EDTA, and phen. These studies suggest a new class of multifunctional molecules for the development of chemical tools to unravel metal-associated events in AD and potential therapeutic agents for metat-ion chetation therapy.