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.
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.
Naylor
M A
MA
MRC Radiobiology Unit, Chilton, Didcot, Oxon, UK.
Sutton
B M
BM
Nolan
J
J
O'Neill
P
P
Fielden
E M
EM
Adams
G E
GE
Stratford
I J
IJ
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
D000970:Antineoplastic Agents; D011719:Pyrazines; C087409:RB 90740