title: 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.
abstract: OBJECTIVE
  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
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: MRC Radiobiology Unit, Chilton, Didcot, Oxon, UK.
authors.forename: M A
authors.initials: MA
authors.lastname: Naylor
authors.forename: B M
authors.initials: BM
authors.lastname: Sutton
authors.forename: J
authors.initials: J
authors.lastname: Nolan
authors.forename: P
authors.initials: P
authors.lastname: O'Neill
authors.forename: E M
authors.initials: EM
authors.lastname: Fielden
authors.forename: G E
authors.initials: GE
authors.lastname: Adams
authors.forename: I J
authors.initials: IJ
authors.lastname: Stratford
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000378:metabolism* / Q000494:pharmacology; D015687:Cell Hypoxia; D006801:Humans; D006863:Hydrogen-Ion Concentration; D051379:Mice; D010084:Oxidation-Reduction; D010777:Photochemistry; D011719:Pyrazines / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D011719:Pyrazines; C087409:RB 90740