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
Ma. Naylor et al., 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, International journal of radiation oncology, biology, physics, 29(2), 1994, pp. 333-337
Citations number
8
Categorie Soggetti
Oncology,"Radiology,Nuclear Medicine & Medical Imaging
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
.