Indolequinone bioreductive drugs: kinetic factors which influence selectivity for hypoxia

The factors influencing the kinetics of the oxygen-sensitive reduction of i ndolequinones, including those bearing leaving groups in the (indol-3-yl)me thyl position, have been studied. The hydroquinones derived from some repre sentative indolequinones were found to autoxidize slowly in oxygenated solu tion at rates (effective rate constant with O-2 similar to 40-300 M-1 s(-1) ) that cannot compete with the reductive elimination of leaving groups. The rates of reaction between hydroquinone and O-2 were even slower in the pre sence of similar to 4 mu M superoxide dismutase (effective rate constant si milar to 2-7 M-1 s(-1)), indicating the role of superoxide radicals in hydr oquinone autoxidation. Since the release of the leaving groups from the hyd roquinones is not significantly oxygen-sensitive, tumour selectivity requir es specific reduction by enzymes that are overexpressed in some tumours. Co nversely, the release of leaving groups from semiquinone radicals is inhibi ted by oxygen too efficiently unless the semiquinone reacts with targets on a timescale of milliseconds. Modification of redox properties has been exp lored with the aim of changing this oxygen sensitivity. The new 2-phenylind olequinones are similar to 60-100 mV higher in reduction potential than 2-a lkyl 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 toxi city of EO9 and related compounds towards hypoxic rather than anoxic cells.