Indolequinone antitumour agents: correlation between quinone structure and rate of metabolism by recombinant human NAD(P)H : quinone oxidoreductase

A series of indolequinones bearing a range of substituents at the (indol-2-yl)methyl position has been synthesized. The ability of these indolequinones to act as substrates for recombinant human NAD(P)H:quinone oxidoreductase (NQO1), a two-electron reductase upregulated in tumour cells, was determined, along with their toxicity to an isogenic tumour cell line pair that is differentiated as either NQO1-expressing cells (BE-NQ) or NQO1-null cells (BE-WT). Overall, the 2-substituted indolequinones were relatively poor substrates for NQO1. Hydroxymethyl groups at C-2 led to higher rates of reduction, a finding that was observed previously with 3-hydroxymethylated indolequinones. Predictably, the best substrate had an electron-withdrawing ester group at the indole-2-position. The indolequinones were generally non-toxic to both cell lines with the exception of those quinones that had methylaziridine groups at the indole-5-position. These compounds could form DNA cross-links when activated by reduction and were up to 3-fold more toxic to the BE-NQ cells than the BE-WT cells.