Indolequinone bioreductive drugs: kinetic factors which influence selectivity for hypoxia.
Кључне речи
Апстрактан
The factors influencing the kinetics of the oxygen-sensitive reduction of indolequinones, including those bearing leaving groups in the (indol-3-yl)methyl position, have been studied. The hydroquinones derived from some representative indolequinones were found to autoxidize slowly in oxygenated solution at rates (effective rate constant with O2 approximately 40-300 M-1 s-1) that cannot compete with the reductive elimination of leaving groups. The rates of reaction between hydroquinone and O2 were even slower in the presence of approximately 4 microM superoxide dismutase (effective rate constant approximately 2-7 M-1 s-1), indicating the role of superoxide radicals in hydroquinone autoxidation. Since the release of the leaving groups from the hydroquinones is not significantly oxygen-sensitive, tumour selectivity requires specific reduction by enzymes that are overexpressed in some tumours. Conversely, the release of leaving groups from semiquinone radicals is inhibited by oxygen too efficiently unless the semiquinone reacts with targets on a timescale of milliseconds. Modification of redox properties has been explored with the aim of changing this oxygen sensitivity. The new 2-phenylindolequinones are approximately 60-100 mV higher in reduction potential than 2-alkyl derivatives but this is insufficient to decrease the rate of electron transfer from semiquinone to oxygen to a degree which might confer hypoxia-selective cytotoxicity. These results are discussed in the context of toxicity of EO9 and related compounds towards hypoxic rather than anoxic cells.