Development of 3-hydroxycinnamamide-based HDAC inhibitors with potent in vitro and in vivo anti-tumor activity

Eur J Med Chem. 2015 Jan 7:89:628-37. doi: 10.1016/j.ejmech.2014.10.077. Epub 2014 Oct 29.

Abstract

Inhibition of histone deacetylases (HDACs) has diverse effects on cell function, such as causing differentiation, growth arrest and apoptosis in nearly all types of tumor cell lines. In our previous work, we have designed and synthesized a novel series of 4-hydroxycinnamamide-based and 3-hydroxycinnamamide-based HDAC inhibitors (HDACIs), among which, 3-hydroxycinnamamide-based HDACIs 1a-1c exhibited moderate inhibition against HDACs. In this article, we report the development of a more potent class of 3-hydroxycinnamamide-based HDACIs, compound 7o exhibited much higher pan-HDAC inhibitory activity than positive control SAHA. In addition, compound 7h showed excellent in vitro growth inhibitory activity against more than ten cell lines and induced U937 cells apoptosis in micromolar concentration. In vivo assay in U937 xenograft model identified compound 7h as a potent, orally active HDACI.

Keywords: Anti-tumor drugs; Antiproliferative activity; HDACIs; HDACs; In vivo oral activity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / chemical synthesis
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology*
  • Apoptosis / drug effects
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Dose-Response Relationship, Drug
  • Drug Screening Assays, Antitumor
  • Histone Deacetylase Inhibitors / chemical synthesis
  • Histone Deacetylase Inhibitors / chemistry
  • Histone Deacetylase Inhibitors / pharmacology*
  • Histone Deacetylases / metabolism*
  • Humans
  • Hydroxamic Acids / chemical synthesis
  • Hydroxamic Acids / chemistry
  • Hydroxamic Acids / pharmacology*
  • Indoles / chemical synthesis
  • Indoles / chemistry
  • Indoles / pharmacology*
  • Molecular Structure
  • Structure-Activity Relationship

Substances

  • Antineoplastic Agents
  • Histone Deacetylase Inhibitors
  • Hydroxamic Acids
  • Indoles
  • N-(1-(3-(3-(hydroxyamino)-3-oxoprop-1-en-1-yl)phenoxy)-3-(1H-indol-3-yl)propan-2-yl)-4-methoxybenzamide
  • Histone Deacetylases