Discovery of aliphatic-chain hydroxamates containing indole derivatives with potent class I histone deacetylase inhibitory activities

Shi Wei Chao, Liang Chieh Chen, Chia Chun Yu, Chang Yi Liu, Tony Eight Lin, Jih Hwa Guh, Chen Yu Wang, Chun Yung Chen, Kai Cheng Hsu, Wei Jan Huang

Research output: Contribution to journalArticle

10 Citations (Scopus)


Histone deacetylase (HDAC) is a validated drug target for various diseases. This study combined indole recognition cap with SAHA, an FDA-approved HDAC inhibitor used to treat cutaneous T-cell lymphoma (CTCL). The structure activity relationship of the resulting compounds that inhibited HDAC was disclosed as well. Some compounds exhibited much stronger inhibitory activities than SAHA. We identified two meta-series compounds 6j and 6k with a two-carbon linker had IC50 values of 3.9 and 4.5 nM for HDAC1, respectively. In contrast, the same oriented compounds with longer carbon chain linkers showed weaker inhibition. The result suggests that the linker chain length greatly contributed to enzyme inhibitory potency. In addition, comparison of enzyme-inhibiting activity between the compounds and SAHA showed that compounds 6j and 6k displayed higher inhibiting activity for class I (HDAC1, -2, -3 and -8). The molecular docking and structure analysis revealed structural differences with the inhibitor cap and metal-binding regions between the HDAC isozymes that affect interactions with the inhibitors and play a key role for selectivity. Further biological evaluation showed multiple cellular effects associated with compounds 6j- and 6k-induced HDAC inhibitory activity.

Original languageEnglish
Pages (from-to)792-805
Number of pages14
JournalEuropean Journal of Medicinal Chemistry
Publication statusPublished - Jan 1 2018



  • Histone deacetylase
  • Indole
  • Isozyme
  • Molecular docking
  • Structure activity relationship

ASJC Scopus subject areas

  • Pharmacology
  • Drug Discovery
  • Organic Chemistry

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