Synthesis and evaluation of 7,8-dehydrorutaecarpine derivatives as potential multifunctional agents for the treatment of Alzheimer's disease

Eur J Med Chem. 2013 May:63:299-312. doi: 10.1016/j.ejmech.2013.02.014. Epub 2013 Feb 26.

Abstract

A series of 7,8-dehydrorutaecarpine derivatives were synthesized and characterized as potential multifunctional agents for treatment of Alzheimer's disease (AD). All of these synthetic compounds showed high acetylcholinesterase (AChE) inhibitory activity with IC50 values ranged from 0.60 to 196.7 nM, and good selectivity for AChE over butyrylcholinesterase (BuChE) (125- to 3225-fold). A Lineweaver-Burk plot and molecular modeling study indicated these compounds could bind to both catalytic active site and the peripheral anionic site of AChE. Besides, compounds showed higher activity of inhibiting AChE-induced amyloid-beta (Aβ) aggregation than curcumin, higher anti-oxidative activity than Trolox, and could also be good metal chelators. Considering their low cytotoxicity, our results indicated that these derivatives provide good templates for developing new multifunctional agents for AD treatment.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylcholinesterase / chemistry
  • Acetylcholinesterase / metabolism*
  • Alzheimer Disease / metabolism*
  • Amyloid beta-Peptides / antagonists & inhibitors*
  • Amyloid beta-Peptides / metabolism
  • Antioxidants / chemical synthesis
  • Antioxidants / chemistry
  • Antioxidants / pharmacology
  • Biocatalysis / drug effects
  • Butyrylcholinesterase / chemistry
  • Butyrylcholinesterase / metabolism*
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Chelating Agents / chemical synthesis
  • Chelating Agents / chemistry
  • Chelating Agents / pharmacology
  • Cholinesterase Inhibitors / chemical synthesis*
  • Cholinesterase Inhibitors / chemistry
  • Cholinesterase Inhibitors / pharmacology*
  • Dose-Response Relationship, Drug
  • Humans
  • Indole Alkaloids / chemical synthesis
  • Indole Alkaloids / chemistry
  • Indole Alkaloids / pharmacology
  • Inhibitory Concentration 50
  • Kinetics
  • Models, Chemical
  • Models, Molecular
  • Molecular Structure
  • Peptide Fragments / antagonists & inhibitors
  • Peptide Fragments / metabolism
  • Protein Binding
  • Protein Structure, Tertiary
  • Quinazolines / chemical synthesis
  • Quinazolines / chemistry
  • Quinazolines / pharmacology

Substances

  • Amyloid beta-Peptides
  • Antioxidants
  • Chelating Agents
  • Cholinesterase Inhibitors
  • Indole Alkaloids
  • Peptide Fragments
  • Quinazolines
  • amyloid beta-protein (1-42)
  • rutecarpine
  • Acetylcholinesterase
  • Butyrylcholinesterase