RADIOLYTIC AND PHOTOCHEMICAL REDUCTION OF THE HYPOXIC CYTOTOXIN ,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

Purpose: 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: Redu ction of I has been initiated radiolytically and photochemically in aq ueous solution and the products isolated and characterized by high per formance liquid chromatography (HPLC). Results: Radiolytic reduction o f 1 leads to the formation of the 2-electron reduced product, 2. The s toichiometry of the reduction is pH dependent, increasing from 1 to 2 with increasing pH, but independent of the presence of formate or 2-me thyl 2-propanol in the reduction mixture. A dimerization product, 3, i s also found, which is produced in greater yields at lower pH (< 6). P hotochemical reduction of 1 to 2 was also found to be facile. Photolys is of 1 also leads to a deoxyribonucleic acid cleavage reaction. Concl usion: Since 2 is not cytotoxic towards hypoxic cells at concentration s at which 1 is toxic, a probable candidate as the cytotoxic species u nder hypoxic conditions is the 1-electron reduced intermediate species .