Novel sampangine derivatives as potent inhibitors of Cu2+-mediated amyloid-β protein aggregation, oxidative stress and inflammation.

Abstract

A series of 11-substituted sampangine derivatives have been designed, synthesized, and tested for their ability to inhibit cholinesterase. Their chelating ability and selectivity for Cu2+ over other biologically relevant metal ions were demonstrated by isothermal titration calorimetry. Their blood-brain barrier permeability was also tested by parallel artificial membrane permeation assay. Among the synthesized derivatives, compound 11 with the strong anti-acetylcholinesterase activity, high blood-brain barrier penetration ability and high binding affinity to Cu2+ was selected for further research. Western blotting analysis, transmission electron microscopy, DCFH-DA assay and paralysis experiment indicated that compound 11 suppressed the formation of Cu2+-Aβ complexes, alleviated the Cu2+ induced neurotoxicity and inhibited the production of ROS catalyzed by Cu2+ in Aβ42 transgenic C. elegans. Moreover, compound 11 also inhibited the expressions of proinflammatory cytokines, such as NO, TNF-α, IL-6 and IL-1β, induced by Cu2+ + Aβ1-42 in BV2 microglial cells. In general, this work provided new insights into the design and development of potent metal-chelating agents for AD treatment.

• Authors: Xiao-Yan Zou, Ren-Ren Xie, Wei Li, Chun-Ling Su, Yu-Si Chen, Huang Tang
• Journal: International journal of biological macromolecules (Int J Biol Macromol) Vol. 174 Pg. 1-10 (Mar 31 2021) ISSN: 1879-0003 [Electronic] Netherlands
• PMID: 33476619 (Publication Type: Journal Article)
• Copyright: Copyright © 2018 Elsevier B.V. All rights reserved.

Chemical References

• Alkaloids
• Amyloid beta-Peptides
• Chelating Agents
• Cholinesterase Inhibitors
• Cytokines
• Heterocyclic Compounds, 4 or More Rings
• Naphthyridines
• Peptide Fragments
• Protein Aggregates
• Reactive Oxygen Species
• Copper
• Acetylcholinesterase
• Cholinesterases
• sampangine

Topics

• Acetylcholinesterase (metabolism)
• Alkaloids (chemistry, metabolism)
• Alzheimer Disease (drug therapy, metabolism)
• Amyloid beta-Peptides (chemistry)
• Animals
• Animals, Genetically Modified
• Blood-Brain Barrier (metabolism)
• Caenorhabditis elegans (metabolism)
• Calorimetry (methods)
• Cell Line
• Chelating Agents (chemistry)
• Cholinesterase Inhibitors (chemical synthesis, chemistry)
• Cholinesterases (metabolism)
• Copper (chemistry)
• Cytokines
• Heterocyclic Compounds, 4 or More Rings (chemistry, metabolism)
• Inflammation
• Microglia
• Naphthyridines (chemistry, metabolism)
• Oxidative Stress (drug effects)
• Peptide Fragments (metabolism)
• Protein Aggregates
• Reactive Oxygen Species (metabolism)