Discovery of potent histone deacetylase inhibitors with modified phenanthridine caps

J Enzyme Inhib Med Chem. 2021 Dec;36(1):707-718. doi: 10.1080/14756366.2021.1892089.

Abstract

In discovery of novel HDAC inhibitory with anticancer potency, pharmacophores of phenanthridine were introduced to the structure of HDAC inhibitors. Fatty and aromatic linkers were evaluated for their solubility and activity. Both enzyme inhibitory and in vitro antiproliferative (against U937 cells) screening results revealed better activities of compounds with aromatic linker than molecules with fatty linker. Compared with SAHA (IC50 values of 1.34, 0.14, 2.58, 0.67 and 18.17 µM), molecule Fb-4 exhibited 0.87, 0.09, 0.32, 0.34 and 17.37 µM of IC50 values against K562, U266, MCF-7, U937 and HEPG2 cells, respectively. As revealed by cell cycle and apoptotic analysis, induction of G2/M phase arrest and apoptosis plays an important role in the inhibition of MCF-7 cells by Fb-4. Generally, a potent HDAC inhibitor was developed in the present study which could be utilised as a lead compound for further anticancer drug design.

Keywords: Histone deacetylase; anticancer; inhibitor; linker; phenanthridine.

MeSH terms

  • Antineoplastic Agents / chemical synthesis
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology*
  • Apoptosis / drug effects
  • Cell Cycle Checkpoints / drug effects
  • Cell Proliferation / drug effects
  • Dose-Response Relationship, Drug
  • Drug Discovery*
  • Drug Screening Assays, Antitumor
  • Histone Deacetylase Inhibitors / chemical synthesis
  • Histone Deacetylase Inhibitors / chemistry
  • Histone Deacetylase Inhibitors / pharmacology*
  • Histone Deacetylases / metabolism*
  • Humans
  • Molecular Structure
  • Phenanthridines / chemical synthesis
  • Phenanthridines / chemistry
  • Phenanthridines / pharmacology*
  • Structure-Activity Relationship
  • Tumor Cells, Cultured

Substances

  • Antineoplastic Agents
  • Histone Deacetylase Inhibitors
  • Phenanthridines
  • Histone Deacetylases

Grants and funding

This work was supported by Natural Foundation of Shandong Province [Youth Found, Grant No. ZR2019QH005, ZR2019BH068], Science and Technology Support Plan for Youth Innovation in Universities of Shandong Province [Grant No. 2019KJM001], National Natural Science Foundation of China [Youth Found, Grant No. 81803343, 81903468].