Site-activated multifunctional chelator with acetylcholinesterase and neuroprotective-neurorestorative moieties for Alzheimer's therapy.
A novel strategy to develop site-activated multifunctional chelators for targeting multiple etiologies of Alzheimer's disease is reported. The novel prochelator HLA20A with improved cytotoxicity shows little affinity for metal ions until it is activated by binding and inhibiting acetylcholinesterase (AChE), releasing an active chelator HLA20 that modulates amyloid precursor protein (APP) regulation and beta-amyloid (Abeta) reduction, suppresses oxidative stress, and passivates excess metal ions (Fe, Cu, and Zn) in the brain.
Zheng
Hailin
H
Department of Organic Chemistry, the Weizmann Institute of Science, Rehovot 76100, Israel.
Youdim
Moussa B H
MB
Fridkin
Mati
M
D000110:Acetylcholinesterase / Q000378:metabolism*; D000544:Alzheimer Disease / Q000188:drug therapy*; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002614:Chelating Agents / Q000737:chemistry* / Q000494:pharmacology* / Q000633:toxicity; D002800:Cholinesterase Inhibitors / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D015195:Drug Design; D006801:Humans; D006912:Hydroxyquinolines / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use / Q000633:toxicity; D008670:Metals / Q000737:chemistry; D018696:Neuroprotective Agents / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D010879:Piperazines / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use / Q000633:toxicity; D011355:Prodrugs / Q000737:chemistry / Q000494:pharmacology / Q000633:toxicity; D051381:Rats
D002614:Chelating Agents; D002800:Cholinesterase Inhibitors; D006912:Hydroxyquinolines; D008670:Metals; D018696:Neuroprotective Agents; D010879:Piperazines; D011355:Prodrugs; C505060:5-((4-prop-2-ynylpiperazin-1-yl)methyl)quinolin-8-ol; D000110:Acetylcholinesterase