title: Site-activated chelators targeting acetylcholinesterase and monoamine oxidase for Alzheimer's therapy.
abstract: Chelators have the potential to treat the underlying cause of Alzheimer's disease (AD), but their therapeutic use is hampered by their poor targeting and poor permeability to the brain and/or toxic effects. Here, we report a new strategy for designing site-activated chelators targeting both acetylcholinesterase (AChE) and monoamine oxidase (MAO). We demonstrated that our lead 2 inhibited both AChE and MAO in vitro, but with little affinity for metal (Fe, Cu, and Zn) ions. Compound 2 can be activated by inhibition of AChE to release an active chelator M30. M30 has been shown to be able to modulate amyloid precursor protein regulation and beta-amyloid reduction, suppress oxidative stress, and passivate excess metal ions (Fe, Cu, and Zn). Compound 2 was less cytotoxic and more lipophilic than the brain-permeable chelator M30. Our new strategy is relatively simple and generally produces small and simple molecules with drug-like properties; it thus holds a potential use in designing site-activated multifunctional chelators with safer and more efficacious properties for treating other metal-related diseases such as Parkinson's disease and cancer where specific elimination of metals in cancer cells is required.
authors.affiliation: Department of Organic Chemistry, The Weizmann Institute of Science, Rehovot, Israel.
authors.forename: Hailin
authors.initials: H
authors.lastname: Zheng
authors.forename: Moussa B H
authors.initials: MB
authors.lastname: Youdim
authors.forename: Mati
authors.initials: M
authors.lastname: Fridkin
mesh_terms: D000110:Acetylcholinesterase / Q000378:metabolism*; D000544:Alzheimer Disease / Q000188:drug therapy* / Q000201:enzymology; D000818:Animals; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002614:Chelating Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002800:Cholinesterase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D015195:Drug Design; D006801:Humans; D008670:Metals / Q000378:metabolism; D015394:Molecular Structure; D008995:Monoamine Oxidase / Q000378:metabolism*; D008996:Monoamine Oxidase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats
chemical_list: D002614:Chelating Agents; D002800:Cholinesterase Inhibitors; D008670:Metals; D008996:Monoamine Oxidase Inhibitors; D008995:Monoamine Oxidase; D000110:Acetylcholinesterase