Characterisation of radicals formed by the triazine 1,4-dioxide hypoxia-activated prodrug, SN30000

Org Biomol Chem. 2014 Jun 7;12(21):3386-92. doi: 10.1039/c4ob00236a. Epub 2014 Apr 16.

Abstract

The radical species underlying the activity of the bioreductive anticancer prodrug, SN30000, have been identified by electron paramagnetic resonance and pulse radiolysis techniques. Spin-trapping experiments indicate both an aryl-type radical and an oxidising radical, trapped as a carbon-centred radical, are formed from the protonated radical anion of SN30000. The carbon-centred radical, produced upon the one-electron oxidation of the 2-electron reduced metabolite of SN30000, oxidises 2-deoxyribose, a model for the site of damage on DNA which leads to double strand breaks. Calculations using density functional theory support the assignments made.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Hypoxia
  • Cyclic N-Oxides / chemistry*
  • DNA Breaks, Double-Stranded
  • Electron Spin Resonance Spectroscopy
  • Free Radicals / chemistry*
  • Humans
  • Hydrogen-Ion Concentration
  • Kinetics
  • Prodrugs / chemistry*
  • Pulse Radiolysis
  • Quantum Theory
  • Temperature
  • Tirapazamine
  • Triazines / chemistry*

Substances

  • CEN-209
  • Cyclic N-Oxides
  • Free Radicals
  • Prodrugs
  • Triazines
  • Tirapazamine