Design, synthesis and activity evaluation of indole-based double - Branched HDAC1 inhibitors

Bioorg Med Chem. 2019 Apr 15;27(8):1595-1604. doi: 10.1016/j.bmc.2019.03.008. Epub 2019 Mar 4.

Abstract

Histone deacetylases inhibitors (HDACIs) represents effective treatments for cancer. In continuing our efforts to develop novel and potent HDACIs, a series of N-hydroxycinnamamide-based HDACIs with aromatic ring and various aliphatic linker have been successfully designed and synthesized. Biological evaluations established that compounds 4h, 4i, 4j, 4l, 4r showed superior inhibition on histone deacetylase and antiproliferative activity in some solid tumor cell lines [HeLa, SK-N-BE(2), PC-3] compared to the known inhibitor SAHA. Among these analogs, 4l exhibited selectivity to HDAC1.

Keywords: Antiproliferative activity; HDAC inhibitors; Molecular docking; Selectivity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Binding Sites
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Drug Design*
  • Histone Deacetylase 1 / antagonists & inhibitors*
  • Histone Deacetylase 1 / metabolism
  • Histone Deacetylase Inhibitors / chemical synthesis*
  • Histone Deacetylase Inhibitors / metabolism
  • Histone Deacetylase Inhibitors / pharmacology
  • Humans
  • Indoles / chemistry
  • Indoles / metabolism
  • Indoles / pharmacology
  • Molecular Docking Simulation
  • Protein Isoforms / antagonists & inhibitors
  • Protein Isoforms / metabolism
  • Protein Structure, Tertiary
  • Structure-Activity Relationship

Substances

  • Histone Deacetylase Inhibitors
  • Indoles
  • Protein Isoforms
  • HDAC1 protein, human
  • Histone Deacetylase 1