Structure optimization and preliminary bioactivity evaluation of N-hydroxybenzamide-based HDAC inhibitors with Y-shaped cap

Bioorg Med Chem. 2018 May 1;26(8):1859-1868. doi: 10.1016/j.bmc.2018.02.033. Epub 2018 Feb 18.

Abstract

Histone deacetylase inhibitors (HDACIs) are effective small molecules in the treatment of human cancers. In our continuing efforts to develop novel N-hydroxyterephthalamide-based HDACIs, herein we report the design and development of a new class of N-hydroxybenzamide-based HDACIs. In this new class of analogs, we inserted an ethylene moiety in the linker and used indole as a part of the Y-shaped cap group. Biological characterization identified compounds 4o, 4p, 4q and 4t to show improved HDAC inhibition, while no isoform selectivity for HDACs was observed. These compounds also exhibited improved anti-proliferative activity against multiple cancer cell lines when compared to their parent compound and positive control SAHA.

Keywords: Antiproliferative activity; HDAC inhibitors; Molecular docking; Y-shaped cap.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / chemical synthesis*
  • Antineoplastic Agents / metabolism
  • Antineoplastic Agents / pharmacology
  • Benzamides / chemistry*
  • Benzamides / metabolism
  • Benzamides / pharmacology
  • Binding Sites
  • Cell Proliferation / drug effects
  • HeLa Cells
  • Histone Deacetylase Inhibitors / chemical synthesis*
  • Histone Deacetylase Inhibitors / metabolism
  • Histone Deacetylase Inhibitors / pharmacology
  • Histone Deacetylases / chemistry
  • Histone Deacetylases / metabolism*
  • Humans
  • Molecular Conformation
  • Molecular Docking Simulation
  • Protein Isoforms / antagonists & inhibitors
  • Protein Isoforms / metabolism
  • Structure-Activity Relationship

Substances

  • Antineoplastic Agents
  • Benzamides
  • Histone Deacetylase Inhibitors
  • Protein Isoforms
  • benzamide
  • Histone Deacetylases