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

Yan He; Pei-Fen Yao; Shuo-bin Chen; Zhi-hong Huang; Shi-Liang Huang; Jia-Heng Tan; Ding Li; Lian-Quan Gu; Zhi-Shu Huang

doi:10.1016/j.ejmech.2013.02.014

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.

Authors

Yan He¹, Pei-Fen Yao, Shuo-bin Chen, Zhi-hong Huang, Shi-Liang Huang, Jia-Heng Tan, Ding Li, Lian-Quan Gu, Zhi-Shu Huang

Affiliation

¹ School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, People's Republic of China.

PMID: 23501115
DOI: 10.1016/j.ejmech.2013.02.014

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