Synthesis and biological evaluation of 2-benzoylpyridine thiosemicarbazones in a dimeric system: structure-activity relationship studies on their anti-proliferative and iron chelation efficacy

J Inorg Biochem. 2014 Dec:141:43-54. doi: 10.1016/j.jinorgbio.2014.07.020. Epub 2014 Aug 7.

Abstract

Thiosemicarbazone chelators represent an exciting class of biologically active compounds that show great potential as anti-tumor agents. Our previous studies demonstrated the potent anti-tumor activity of the 2'-benzoylpyridine thiosemicarbazone series. While extensive studies have been performed on monomeric thiosemicarbazone compounds, dimeric thiosemicarbazone chelators have received comparatively less attention. Thus, it was of interest to investigate the anti-proliferative activity and iron chelation efficacy of dimeric thiosemicarbazones. Two classes of dimeric thiosemicarbazones were designed and synthesized. The first class consisted of two benzoylpyridine-based thiosemicarbazone units connected via a hexane or dodecane alkyl bridge, while the second class of dimer consisted of two thiosemicarbazones attached to a 2,6-dibenzoylpyridine core. These dimeric ligands demonstrated greater anti-proliferative activity than the clinically used iron chelator, desferrioxamine. This study highlights the importance of optimal lipophilicity as a factor influencing the cytotoxicity and iron chelation efficacy of these chelators.

Keywords: Dimer; Iron; Lipophilicity; Thiosemicarbazone.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / chemical synthesis*
  • Antineoplastic Agents / pharmacology
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Cell Survival / drug effects
  • Crystallography, X-Ray
  • Dimerization
  • Humans
  • Hydrophobic and Hydrophilic Interactions
  • Iron / chemistry*
  • Iron / metabolism
  • Iron Chelating Agents / chemical synthesis*
  • Iron Chelating Agents / pharmacology
  • Kinetics
  • Pyridines / chemical synthesis*
  • Pyridines / pharmacology
  • Structure-Activity Relationship
  • Thiosemicarbazones / chemical synthesis*
  • Thiosemicarbazones / pharmacology

Substances

  • Antineoplastic Agents
  • Iron Chelating Agents
  • Pyridines
  • Thiosemicarbazones
  • Iron