Dual-acting histone deacetylase-topoisomerase I inhibitors

Bioorg Med Chem Lett. 2013 Jun 1;23(11):3283-7. doi: 10.1016/j.bmcl.2013.03.108. Epub 2013 Apr 4.


Current chemotherapy regimens are comprised mostly of single-target drugs which are often plagued by toxic side effects and resistance development. A pharmacological strategy for circumventing these drawbacks could involve designing multivalent ligands that can modulate multiple targets while avoiding the toxicity of a single-targeted agent. Two attractive targets, histone deacetylase (HDAC) and topoisomerase I (Topo I), are cellular modulators that can broadly arrest cancer proliferation through a range of downstream effects. Both are clinically validated targets with multiple inhibitors in therapeutic use. We describe herein the design and synthesis of dual-acting histone deacetylase-topoisomerase I inhibitors. We also show that these dual-acting agents retain activity against HDAC and Topo I, and potently arrest cancer proliferation.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Camptothecin / chemistry
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • DNA Topoisomerases, Type I / chemistry*
  • DNA Topoisomerases, Type I / metabolism
  • Drug Design
  • HeLa Cells
  • Histone Deacetylase Inhibitors / chemical synthesis
  • Histone Deacetylase Inhibitors / chemistry*
  • Histone Deacetylase Inhibitors / toxicity
  • Histone Deacetylases / chemistry*
  • Histone Deacetylases / metabolism
  • Humans
  • Protein Isoforms / antagonists & inhibitors
  • Protein Isoforms / metabolism
  • Structure-Activity Relationship
  • Topoisomerase I Inhibitors / chemical synthesis
  • Topoisomerase I Inhibitors / chemistry*
  • Topoisomerase I Inhibitors / toxicity


  • Histone Deacetylase Inhibitors
  • Protein Isoforms
  • Topoisomerase I Inhibitors
  • Histone Deacetylases
  • DNA Topoisomerases, Type I
  • Camptothecin