ELECTRON-TRANSFER REACTIONS IN RB90745, A BIOREDUCTIVE DRUG HAVING BOTH AROMATIC N-OXIDE AND NITROARENE MOIETIES

The bifunctional hypoxia-specific cytotoxin RB90745, has a nitroimidaz ole moiety attached to an imidazo[1,2,-a]quinoxaline mono-N-oxide with a spacer/linking group. The reduction chemistry of the drug was studi ed by pulse radiolysis using the one electron reductant CO2.- As N-oxi des and nitro compounds react with CO2.- at diffusion controlled rates , initial reaction produced a mixture of the nitro radical (lambda(max ) 410 nm) and the N-oxide radical (lambda(max) 550 nm) in a few micros econds. Subsequently an intramolecular electron transfer (IET) was obs erved (k = 1.0 +/- 0.25 x 10(3) s(-1) at pH 5-9), from the N-oxide to the more electron-affinic nitro group. This was confirmed by the first order decay rate of the radical at 550 nm and formation at 410 nm, wh ich was independent of both the concentration of the parent compound a nd the radicals. The rates of electron transfer and the decay kinetics of the nitro anion radicals were pH dependent and three different pK( a)s could be estimated for the one electron reduced species: 5.6 (nitr oimidazole group) and 4.3, and 7.6 (N-oxide function). The radicals re act with oxygen with rate constants of 3.1 x 10(7) and 2.8 x 10(6) dm( 3) mol(-1)s(-1) observed at 575 nm and 410 nm respectively. Steady sta te radiolysis studies indicated four electron stoichiometry for the re duction of the compound.