Molecular mechanism of the enzymatic oxidation investigated for imidazoacridinone antitumor drug, C-1311

Biochem Pharmacol. 2003 Nov 1;66(9):1727-36. doi: 10.1016/s0006-2952(03)00477-5.

Abstract

The imidazoacridinone derivative, C-1311, is an antitumor agent that has been under phase I of clinical trial. The work presented here aims to elucidate the molecular mechanism of the enzymatic oxidative activation of this drug in such a model metabolic system, where the covalent binding to DNA was previously demonstrated. The oxidative activation of C-1311 was performed with HRP/H(2)O(2) and MPO/H(2)O(2) systems. The obtained final products of such transformations were separated and analysed by HPLC. The structures of the products were identified by means of ESI-MS and NMR. It was demonstrated that C-1311 was oxidised with HRP and MPO in the manner dependent on the drug:H(2)O(2) ratio and the drug was more susceptible to HRP oxidation than to MPO. Structural studies showed compounds C0 and C1 to be the result of dealkylation, which occurred in the amino groups of the side chain. The structures of C3 and C4 products were identified as dimers, whose monomers held the imidazoacridinone core. The activation of the imidazoacridinone ring system in position ortho to 8-hydroxyl group was necessary to form such dimers. We suggest that similar mechanism of C-1311 activation should occur in the presence of DNA when, instead of the dimer formation, the covalent binding to DNA, showed earlier for this drug, was formed. Since peroxidase-type enzymes are present in the cell nucleus of tumour cells the activation mechanisms of the C-1311 proposed here may be expected to take place in the cellular environment in vivo.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aminoacridines / chemistry
  • Aminoacridines / metabolism*
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / metabolism*
  • Biotransformation
  • Chromatography, High Pressure Liquid
  • Horseradish Peroxidase / metabolism*
  • Magnetic Resonance Spectroscopy
  • Oxidation-Reduction
  • Peroxidase / metabolism*
  • Pharmaceutical Preparations
  • Spectrometry, Mass, Electrospray Ionization

Substances

  • Aminoacridines
  • Antineoplastic Agents
  • Pharmaceutical Preparations
  • Horseradish Peroxidase
  • Peroxidase
  • C 1311