Indolequinone antitumor agents: Correlation between quinone structure and rate of metabolism by recombinant human NAD(P)H : quinone oxidoreductase. Part 2
E. Swann et al., Indolequinone antitumor agents: Correlation between quinone structure and rate of metabolism by recombinant human NAD(P)H : quinone oxidoreductase. Part 2, J MED CHEM, 44(20), 2001, pp. 3311-3319
A series of indolequinones bearing various functional groups has been synth
esized, and the effects of substituents on the metabolism of the quinones.
by recombinant human NAD(P)H: quinone oxidoreductase (NQO1) were studied. I
ndolequinones were selected for study on the basis of the X-ray crystal str
ucture of the human enzyme, and were designed to probe the effect of substi
tuents particularly at N-1. Metabolism of the quinones. by NQO1 revealed th
at, in general, compounds with electron-withdrawing groups at the indole 3-
position were among the best substrates, and that groups larger than methyl
at N-1 are clearly tolerated. Compounds with a leaving group at the 3-indo
lyl methyl position generally inactivated the enzyme. The toxicity toward h
uman colon carcinoma cells with either no detectable activity (BE-WT) or hi
gh NQO1 activity (BE-NQ) was also studied in representative quinones. The m
ost toxic compounds were those with a leaving group at the C-3 position; th
ese compounds were 1.1-5.3-fold more toxic. to the BE-NQ than the BE-WT cel
ls.