Synthesis and multitarget biological profiling of a novel family of rhein derivatives as disease-modifying anti-Alzheimer agents

J Med Chem. 2014 Mar 27;57(6):2549-67. doi: 10.1021/jm401824w. Epub 2014 Mar 10.

Abstract

We have synthesized a family of rhein-huprine hybrids to hit several key targets for Alzheimer's disease. Biological screening performed in vitro and in Escherichia coli cells has shown that these hybrids exhibit potent inhibitory activities against human acetylcholinesterase, butyrylcholinesterase, and BACE-1, dual Aβ42 and tau antiaggregating activity, and brain permeability. Ex vivo studies with the leads (+)- and (-)-7e in brain slices of C57bl6 mice have revealed that they efficiently protect against the Aβ-induced synaptic dysfunction, preventing the loss of synaptic proteins and/or have a positive effect on the induction of long-term potentiation. In vivo studies in APP-PS1 transgenic mice treated ip for 4 weeks with (+)- and (-)-7e have shown a central soluble Aβ lowering effect, accompanied by an increase in the levels of mature amyloid precursor protein (APP). Thus, (+)- and (-)-7e emerge as very promising disease-modifying anti-Alzheimer drug candidates.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alzheimer Disease / drug therapy*
  • Amyloid Precursor Protein Secretases / antagonists & inhibitors
  • Amyloid beta-Peptides / antagonists & inhibitors
  • Amyloid beta-Protein Precursor / antagonists & inhibitors
  • Animals
  • Anthraquinones / chemical synthesis*
  • Anthraquinones / pharmacology
  • Aspartic Acid Endopeptidases / antagonists & inhibitors
  • Binding Sites
  • Blood-Brain Barrier / drug effects
  • Cholinesterase Inhibitors / chemical synthesis
  • Cholinesterase Inhibitors / pharmacology
  • Enzyme Inhibitors / chemical synthesis*
  • Enzyme Inhibitors / pharmacology
  • Escherichia coli / metabolism
  • Hippocampus / drug effects
  • Hippocampus / metabolism
  • Humans
  • In Vitro Techniques
  • Kinetics
  • Long-Term Potentiation / drug effects
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Models, Molecular
  • Peptide Fragments / antagonists & inhibitors
  • Stereoisomerism
  • Synapses / metabolism
  • tau Proteins / antagonists & inhibitors

Substances

  • Amyloid beta-Peptides
  • Amyloid beta-Protein Precursor
  • Anthraquinones
  • Cholinesterase Inhibitors
  • Enzyme Inhibitors
  • Peptide Fragments
  • amyloid beta-protein (1-42)
  • tau Proteins
  • Amyloid Precursor Protein Secretases
  • Aspartic Acid Endopeptidases
  • BACE1 protein, human
  • rhein