Cytotoxicity profile of novel sterically hindered platinum(II) complexes with (1R,2R)-N(1),N(2)-dibutyl-1,2-diaminocyclohexane

Eur J Med Chem. 2015:96:187-95. doi: 10.1016/j.ejmech.2015.04.019. Epub 2015 Apr 8.

Abstract

Four Pt(II) complexes of (1R,2R)-N(1),N(2)-dibutyl-1,2-diaminocyclohexane with two alkyl branches as steric hindrance have been designed and synthesized. In vitro cytotoxicity of these compounds indicated complex 4 is a cytotoxic agent more potent than its parent molecule, oxaliplatin, against almost all the tested cell lines. Agarose gel electrophoresis study showed that the kinetic reactivity of complex 4 with DNA is slow down due to the sterically hindered effect, demonstrating that it may possess a different mechanism of action from cisplatin. Flow cytometry results revealed that complex 4 induced apoptosis of tumor cells by blocking the cell-cycle progression in the G2/M phase. Western blot analysis showed it had a similar apoptotic mechanism to cisplatin which could induce apoptosis via a mitochondrial-dependent pathway.

Keywords: Apoptotic mechanism; Platinum (II) complexes; Potent cytotoxicity; Steric hindrance.

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 Cycle / drug effects
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Cyclohexylamines / chemistry
  • Cyclohexylamines / pharmacology*
  • Dose-Response Relationship, Drug
  • Drug Screening Assays, Antitumor
  • Flow Cytometry
  • Humans
  • Molecular Structure
  • Organoplatinum Compounds / chemical synthesis
  • Organoplatinum Compounds / chemistry
  • Organoplatinum Compounds / pharmacology*
  • Structure-Activity Relationship

Substances

  • Antineoplastic Agents
  • Cyclohexylamines
  • N(1),N(2)-dibutyl-1,2-diaminocyclohexane
  • Organoplatinum Compounds