DNA DAMAGING EFFECTS AND VOLTAMMETRIC STUDIES ON THE HYPOXIC CELL TOXIN 3-AMINO-1,2,4-BENZOTRIAZINE-1,4-DIOXIDE, SR4233, AS A FUNCTION OF PH

The compound 3-amino-1,2,4-benzotriazine-1,4-dioxide, SR4233, has recently attracted considerable attention as a possible hypoxic cell radiation sensitizer and cytotoxic agent. The present study examines the influence of pH on the DNA damaging ability of SR4233 upon electrolytic reductive activation, and the corresponding changes in electrochemistry. A Φ X174 double transfection assay has been employed to assess the DNA damaging ability of SR4233 between pH4 to 7. Upon electrolytic reduction the drug was found to be more effective in damaging DNA at acidic pH than at neutral conditions. This indicated that the damaging species was probably protonated. The DNA damaging ability of SR4233, as measured by a viral transfection assay, was linearly related to pH between the values of 4 and 7, and this feature has implications for its potential efficacy in the treatment of hypoxic tumors. The electrochemistry of SR4233 has been examined as a function of pH between the ranges 2 and 10.5. Three investigation techniques have been employed, cyclic voltammetry and differential pulse and dc polarographies. A general shift towards less negative potentials with increasing acidity was found between pH2 and 8.5 giving a linear relationship. The behaviour was found to be relatively invariant at alkaline pH. © 1990.