Small molecule modulators of copper-induced Abeta 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 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.
Hindo
Sarmad S
SS
Department of Chemistry and the Life Sciences Institute, University of Michigan, Ann Arbor, Michigan 48109, USA.
Mancino
Allana M
AM
Braymer
Joseph J
JJ
Liu
Yihong
Y
Vivekanandan
Subramanian
S
Ramamoorthy
Ayyalusamy
A
Lim
Mi Hee
MH
D000544:Alzheimer Disease / Q000188:drug therapy / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000737:chemistry / Q000187:drug effects* / Q000378:metabolism; D045744:Cell Line, Tumor; D002614:Chelating Agents / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D003300:Copper / Q000737:chemistry / Q000378:metabolism*; D015195:Drug Design; D006801:Humans; D007093:Imidazoles / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D010655:Phenylenediamines / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D011725:Pyridines / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use
C546966:2-(4-(dimethylamino)phenyl)imidazo(1,2-a)pyridine-8-ol; D016229:Amyloid beta-Peptides; D002614:Chelating Agents; D007093:Imidazoles; C546967:N1,N1-dimethyl-N4-(pyridin-2-ylmethylene)benzene-1,4-diamine; D010655:Phenylenediamines; D011725:Pyridines; D003300:Copper