Controlling the rates of reductively-activated elimination from the (indol-3-yl)methyl position of indolequinones

A series of substituted 3-(4-nitrophenyloxy)methylindole-4,7-diones (Q) wer e synthesised. The effects of substitution patterns on the indole core on r ates of elimination of 4-nitrophenol as a model for drug release following fragmentation of a phenolic ether linker were studied. After reduction to e ither the radical anion (Q(.-)) or hydroquinone (QH(2)) elimination of 4-ni trophenol occurred from the (indol-3-yl)methyl position. The half-lives of Q(.-) radicals at [O-2]approximate to5 mu mol dm(-3), typical of tumour hyp oxia, were t(1/2)approximate to0.3-1.8 ms, the higher values associated wit h higher reduction potentials. Half-lives for the autoxidation of the QH(2) were markedly longer at the same oxygen concentration (t(1/2)approximate t o8-102 min) and longer still in the presence of 4 mu mol dm(-3) superoxide dismutase (t(1/2)approximate to8-19 h). Although the indolequinones were ab le to eliminate 4-nitrophenol with high efficiency only Q(.-) radicals of t he 3-carbinyl substituted derivatives did so with sufficiently short half-l ives (t(1/2)approximate to 41-2 ms) to compete with electron transfer to ox ygen and therefore have the potential to target the leaving group to hypoxi c tissue. The hydroquinones are not sufficiently oxygen sensitive to preven t the elimination of 4-nitrophenol (t(1/2)approximate to1.5-3.5 s) even at oxygen concentrations expected in normal tissue. By incorporating electron rich substituents at the indolyl carbinyl position it is possible to contro l the rate of reductive fragmentation. This may prove an important factor i n the design of an indolequinone-based bioreductive drug delivery system.