amyloid-beta-peptides and cupric-chloride

The disruption of copper homeostasis and the oxidative stress induced by Cu-amyloids are crucial features of Alzheimer's disease pathology. The copper specific N

Topics: Aminoquinolines; Amyloid beta-Peptides; Ascorbic Acid; Carrier Proteins; Chelating Agents; Chlorides; Copper; Homeostasis; Humans; Molecular Structure; Oxidation-Reduction; Oxidative Stress; Peptide Fragments; Reactive Oxygen Species; Zinc Compounds

Metal-ion misregulation and oxidative stress continue to be components of the continually evolving hypothesis describing the molecular origins of Alzheimer's disease. Therefore, these features are viable targets for synthetic chemists to explore through hybridizations of metal-binding ligands and antioxidant units. To date, the metal-binding unit in potential therapeutic small molecules has largely been inspired by clioquinol with the exception of a handful of heterocyclic small molecules and open-chain systems. Heterocyclic small molecules such as cyclen (1,4,7,10-tetraazacyclododecane) have the advantage of straightforward N-based modifications, allowing the addition of functional groups. In this work, we report the synthesis of a triazine bridged system containing two cyclen metal-binding units and an antioxidant coumarin appendage inspired by nature. This new potential therapeutic molecule shows the ability to bind copper in a unique manner compared to other chelates proposed to treat Alzheimer's disease. DPPH and TEAC assays exploring the activity of N-(2-((4,6-di(1,4,7,10-tetraazacyclododecan-1-yl)-1,3,5-triazin-2-yl)amino)ethyl)-2-oxo-2H-chromene-3-carboxamide (molecule 1) show that the molecule is antioxidant. Cellular studies of molecule 1 indicate a low toxicity (EC

Topics: Amyloid beta-Peptides; Animals; Antioxidants; Benzopyrans; Cell Line, Transformed; Chelating Agents; Copper; Drug Evaluation, Preclinical; Fluorometry; Mice; Models, Molecular; Molecular Docking Simulation; Molecular Structure; Molecular Weight; Neurons; Neuroprotective Agents; Peptide Fragments; Protein Binding; Protein Conformation; Structure-Activity Relationship; Tyrosine

A design strategy to convert a dual-binding site AChE inhibitor into triple functional compounds with promising in vitro profile against multifactorial syndromes, such as Alzheimer's disease, is proposed. The lead compound bis(7)-tacrine (2) was properly modified to confer to the new molecules the ability of chelating metals, involved in the neurodegenerative process. The multifunctional compounds show activity against human AChE, are able to inhibit the AChE-induced amyloid-beta aggregation, and chelate metals, such as iron and copper.

Topics: Acetylcholinesterase; Alzheimer Disease; Amyloid beta-Peptides; Binding Sites; Butyrylcholinesterase; Chelating Agents; Cholinesterase Inhibitors; Copper; Drug Design; Ferric Compounds; Humans; Ligands; Models, Molecular; Peptide Fragments; Structure-Activity Relationship; Tacrine; Thermodynamics