Indolequinone antitumor agents: Correlation between quinone structure and rate of metabolism by recombinant human NAD(P)H : quinone oxidoreductase. Part 2

Citation
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
Citations number
51
Categorie Soggetti
Chemistry & Analysis
Journal title
JOURNAL OF MEDICINAL CHEMISTRY
ISSN journal
00222623 → ACNP
Volume
44
Issue
20
Year of publication
2001
Pages
3311 - 3319
Database
ISI
SICI code
0022-2623(20010927)44:20<3311:IAACBQ>2.0.ZU;2-L
Abstract
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.