Electron transfer reactions in RB90745, a bioreductive drug having both aromatic N-oxide and nitroarene moieties.

Abstract

The bifunctional hypoxia-specific cytotoxin RB90745, has a nitroimidazole moiety attached to an imidazol[1,2-a]quinoxaline mono-N-oxide with a spacer/linking group. The reduction chemistry of the drug was studied by pulse radiolysis using the one electron reductant CO2.-. As N-oxides 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 microseconds. Subsequently an intramolecular electron transfer (IET) was observed (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, which was independent of both the concentration of the parent compound and the radicals. The rates of electron transfer and the decay kinetics of the nitro anion radicals were pH dependent and three different pKas could be estimated for the one electron reduced species: 5.6 (nitroimidazole group) and 4.3, and 7.6 (N-oxide function). The radicals react with oxygen with rate constants of 3.1 x 10(7) and 2.8 x 10(6) dm3 mol-1 s-1 observed at 575 nm and 410 nm respectively. Steady state radiolysis studies indicated four electron stoichiometry for the reduction of the compound.