Indolequinone Antitumor Agents:  Correlation between Quinone Structure and Rate of Metabolism by Recombinant Human NAD(P)H:Quinone Oxidoreductase. Part 2

• Published in: Journal of medicinal chemistry 2001-09, Vol.44 (20), p.3311-3319
• Main Authors: Swann, Elizabeth, Barraja, Paola, Oberlander, Ann M, Gardipee, Walter T, Hudnott, Anna R, Beall, Howard D, Moody, Christopher J
• Format: Article
• Language: English
• Subjects: Antineoplastic agents; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Biological and medical sciences; Chromatography, High Pressure Liquid; Drug Screening Assays, Antitumor; General aspects; Humans; Indoles - chemical synthesis; Indoles - chemistry; Indoles - pharmacology; Inhibitory Concentration 50; Medical sciences; NAD(P)H Dehydrogenase (Quinone) - metabolism; Pharmacology. Drug treatments; Quinones - chemical synthesis; Quinones - chemistry; Quinones - pharmacology; Recombinant Proteins - metabolism; Structure-Activity Relationship; Tumor Cells, Cultured
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm010884c

A series of indolequinones bearing various functional groups has been synthesized, and the effects of substituents on the metabolism of the quinones by recombinant human NAD(P)H:quinone oxidoreductase (NQO1) were studied. Indolequinones were selected for study on the basis of the X-ray crystal structure of the human enzyme, and were designed to probe the effect of substituents particularly at N-1. Metabolism of the quinones by NQO1 revealed that, 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-indolyl methyl position generally inactivated the enzyme. The toxicity toward human colon carcinoma cells with either no detectable activity (BE-WT) or high NQO1 activity (BE-NQ) was also studied in representative quinones. The most toxic compounds were those with a leaving group at the C-3 position; these compounds were 1.1−5.3-fold more toxic to the BE-NQ than the BE-WT cells.