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Radiolytic and photochemical reduction of the hypoxic cytotoxin 1,2-dihydro-8-(4-methylpiperazinyl)-4-phenylimidazo [1,2-a] pyrido [3,2-e] pyrazine 5-oxide (RB90740) and a potential mechanism for hypoxia-selective toxicity.

AbstractPURPOSE:
To study the reduction of RB90740 (1), a fused pyrazine mono-N-oxide that has an oxic:hypoxic cytotoxicity ratio of > 10 in a range of murine and human tumor cells in vitro.
METHODS AND MATERIALS:
Reduction of 1 has been initiated radiolytically and photochemically in aqueous solution and the products isolated and characterized by high performance liquid chromatography (HPLC).
RESULTS:
Radiolytic reduction of 1 leads to the formation of the 2-electron reduced product, 2. The stoichiometry of the reduction is pH dependent, increasing from 1 to 2 with increasing pH, but independent of the presence of formate or 2-methyl 2-propanol in the reduction mixture. A dimerization product, 3, is also found, which is produced in greater yields at lower pH (< 6). Photochemical reduction of 1 to 2 was also found to be facile. Photolysis of 1 also leads to a deoxyribonucleic acid cleavage reaction.
CONCLUSION:
Since 2 is not cytotoxic towards hypoxic cells at concentrations at which 1 is toxic, a probable candidate as the cytotoxic species under hypoxic conditions is the 1-electron reduced intermediate species.
AuthorsM A Naylor, B M Sutton, J Nolan, P O'Neill, E M Fielden, G E Adams, I J Stratford
JournalInternational journal of radiation oncology, biology, physics (Int J Radiat Oncol Biol Phys) Vol. 29 Issue 2 Pg. 333-7 (May 15 1994) ISSN: 0360-3016 [Print] United States
PMID8195029 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)
Chemical References
  • Antineoplastic Agents
  • Pyrazines
  • RB 90740
Topics
  • Animals
  • Antineoplastic Agents (metabolism, pharmacology)
  • Cell Hypoxia
  • Humans
  • Hydrogen-Ion Concentration
  • Mice
  • Oxidation-Reduction
  • Photochemistry
  • Pyrazines (chemistry, metabolism, pharmacology)
  • Tumor Cells, Cultured

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