Small molecule modulators of copper-induced Abeta aggregation

• Published in: Journal of the American Chemical Society Vol. 131; no. 46; pp. 16663 - 16665
• Main Authors: Hindo, Sarmad S, Mancino, Allana M, Braymer, Joseph J, Liu, Yihong, Vivekanandan, Subramanian, Ramamoorthy, Ayyalusamy, Lim, Mi Hee
• Format: Journal Article
• Language: English
• Published: United States 25.11.2009
• Subjects: Alzheimer Disease - drug therapy; Alzheimer Disease - metabolism; Amyloid beta-Peptides - chemistry; Amyloid beta-Peptides - drug effects; Amyloid beta-Peptides - metabolism; Cell Line, Tumor; Chelating Agents - chemistry; Chelating Agents - pharmacology; Chelating Agents - therapeutic use; Copper - chemistry; Copper - metabolism; Drug Design; Humans; Imidazoles - chemistry; Imidazoles - pharmacology; Imidazoles - therapeutic use; Phenylenediamines - chemistry; Phenylenediamines - pharmacology; Phenylenediamines - therapeutic use; Pyridines - chemistry; Pyridines - pharmacology; Pyridines - therapeutic use
• ISSN: 1520-5126
• DOI: 10.1021/ja907045h

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 Abeta 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 Abeta interaction of 1 and 2 was verified by spectroscopic methods. Furthermore, the reactivity of 1 and 2 with Cu(II)-associated Abeta aggregates was investigated. The modulation of Cu(II)-triggered Abeta 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 metal-ion chelation therapy.