Aliphatic amine N-oxides of DNA binding agents as bioreductive drugs

Oncol Res. 1994;6(10-11):533-8.

Abstract

The DNA binding and cytotoxicity of four intercalating agents, namely bis-alkylamino (-N(CH2)2N(CH3)2) substituted anthraquinone, anthrapyrazole and anthracene, and mono (N(CH2)2N(CH3)2) acridinone, have been compared with their respective aliphatic amine N-oxides -N(CH2)2N+(O-)(CH3)2. The results show that, unlike the intercalators, the N-oxides do not bind to DNA. Molecular modelling illustrates that the delta + nature of the intercalator alkylamino side chains in the protonated form allows for an attractive electrostatic interaction with phosphates of the DNA backbone, whereas the delta- partial charge on the N-oxide makes such an interaction not permissible; indeed, the electrostatic interaction with the DNA phosphates will be repulsive. The N-oxides show little or no cytotoxicity against V79 cells at concentrations equimolar to the IC90 (concentration that inhibits 90% of cell proliferation) of the respective intercalators. However, the cytotoxicity of anthrapyrazole N-oxide against hypoxic V79 cells in the presence of an activating system of S9 liver fraction was enhanced significantly. The results indicate that N-oxides of DNA-affinic agents have potential as bioreductive prodrugs, since they possess low aerobic toxicity but under hypoxic conditions can be metabolised to a potent cytotoxic species presumed to be a DNA-binding tertiary amine.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amines / metabolism
  • Amines / pharmacology
  • Animals
  • Antineoplastic Agents / metabolism*
  • Antineoplastic Agents / pharmacology*
  • Cattle
  • Cells, Cultured
  • Computer Simulation
  • Cricetinae
  • Cricetulus
  • DNA, Neoplasm / drug effects*
  • DNA, Neoplasm / metabolism*
  • Intercalating Agents / metabolism*
  • Intercalating Agents / pharmacology*
  • Models, Molecular
  • Oxidation-Reduction
  • Oxides / metabolism
  • Oxides / pharmacology
  • Structure-Activity Relationship

Substances

  • Amines
  • Antineoplastic Agents
  • DNA, Neoplasm
  • Intercalating Agents
  • Oxides