2-(Phenylsulfonyl)quinoline N-hydroxyacrylamides as potent anticancer agents inhibiting histone deacetylase

Eur J Med Chem. 2016 Oct 21:122:92-101. doi: 10.1016/j.ejmech.2016.06.023. Epub 2016 Jun 16.

Abstract

This study reports the design and synthesis of 2-(phenylsulfonyl)quinoline N-hydroxyacrylamides (8a-k). Structure-activity relationship studies focusing on regio-effect of N-hydroxyacrylamide moiety and influence of the sulfonyl linker revealed that N-hydroxy-3-[3-(quinoline-2-sulfonyl)-phenyl]-acrylamide (8f) showed remarkable enzymatic and cellular activity. The GI50 values of 8f for HL-60, HCT116, PC-3, and A549 cells were found to be 0.29, 0.08, 0.15, and 0.27 μM, respectively. The compounds are therefore more potent than FDA approved PXD-101 and SAHA. They also have an effect on the acetylation degree of histone H3 and α-tubulin. In in vivo studies, 8f showed marked inhibition of the growth of HCT116 xenografts.

Keywords: 2-(Phenylsulfonyl)quinoline; Anticancer agents; Histone deacetylase inhibitors.

MeSH terms

  • Animals
  • Antineoplastic Agents / chemistry*
  • Antineoplastic Agents / pharmacology*
  • Apoptosis / drug effects
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Histone Deacetylase Inhibitors / chemistry*
  • Histone Deacetylase Inhibitors / pharmacology*
  • Histone Deacetylases / metabolism*
  • Histones / metabolism
  • Humans
  • Male
  • Mice
  • Quinolines / chemistry*
  • Quinolines / pharmacology*
  • Structure-Activity Relationship
  • Tubulin / metabolism
  • Xenograft Model Antitumor Assays

Substances

  • Antineoplastic Agents
  • Histone Deacetylase Inhibitors
  • Histones
  • Quinolines
  • Tubulin
  • Histone Deacetylases