Design of diarylheptanoid derivatives as dual inhibitors against class IIa histone deacetylase and β-amyloid aggregation

Liang Chieh Chen, Hui Ju Tseng, Chang Yi Liu, Yun Yi Huang, Cheng Chung Yen, Jing Ru Weng, Yeh Lin Lu, Wen Chi Hou, Tony E. Lin, I. Horng Pan, Kuo Kuei Huang, Wei Jan Huang, Kai Cheng Hsu

Research output: Contribution to journalArticlepeer-review

2 Citations (Scopus)

Abstract

Alzheimer's disease (AD) is a progressive neurodegenerative disorder with multiple etiologies. Beta-amyloid (Aβ) self-aggregation and overexpression of class IIa histone deacetylases (HDACs) are strongly implicated with AD pathogenesis. In this study, a series of novel diarylheptanoid derivatives were designed, synthesized and evaluated for use as dual Aβ self-aggregation and class IIa HDAC inhibitors. Among these compounds, 4j, 5c, and 5e displayed effective inhibitions for Aβ self-aggregation, HDAC5 activity and HDAC7 activity with IC50 values of < 10 μM. The compounds contain three common features: (1) a catechol or pyrogallol moiety, (2) a carbonyl linker and (3) an aromatic ring that can function as an HDAC cap and create hydrophobic interactions with Aβ1-42. Furthermore, compounds 4j, 5c, and 5e showed no significant cytotoxicity to human neuroblastoma SH-SY5Y cells and also exhibited neuroprotective effect against H2O2-induced toxicity. Overall, these promising in vitro data highlighted compounds 4j, 5c, and 5e as lead compounds that are worthy for further investigation.

Original languageEnglish
Article number708
JournalFrontiers in Pharmacology
Volume9
Issue numberJUL
DOIs
Publication statusPublished - Jul 3 2018

Keywords

  • Alzheimer's disease
  • Aβ aggregation
  • Dual inhibitors
  • Histone deacetylase
  • Isoform-selective inhibitors

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)

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