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: Hailin Zheng, Moussa B H Youdim, Mati Fridkin
• Journal: ACS chemical biology (ACS Chem Biol) Vol. 5 Issue 6 Pg. 603-10 (Jun 18 2010) ISSN: 1554-8937 [Electronic] United States
• PMID: 20455574 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Chelating Agents
• Cholinesterase Inhibitors
• Metals
• Monoamine Oxidase Inhibitors
• Monoamine Oxidase
• Acetylcholinesterase

Topics

• Acetylcholinesterase (metabolism)
• Alzheimer Disease (drug therapy, enzymology)
• Animals
• Cell Line, Tumor
• Cell Survival (drug effects)
• Chelating Agents (chemical synthesis, chemistry, pharmacology)
• Cholinesterase Inhibitors (chemical synthesis, chemistry, pharmacology)
• Drug Design
• Humans
• Metals (metabolism)
• Molecular Structure
• Monoamine Oxidase (metabolism)
• Monoamine Oxidase Inhibitors (chemical synthesis, chemistry, pharmacology)
• Rats