Natural and synthetic quinones and their reduction by the quinone reductase enzyme NQO1: from synthetic organic chemistry to compounds with anticancer potential

The quinone reductase enzyme NAD(P)H: quinone oxidoreductase 1 (NQO1) is a ubiquitous flavoenzyme that catalyzes the two-electron reduction of quinones. This Perspective briefly reviews the structure and mechanism, physiological role, and upregulation and induction of the enzyme, but focuses on the...

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Bibliographic Details
Published in:Organic & biomolecular chemistry 2008-01, Vol.6 (4), p.637-656
Main Authors: Colucci, Marie A, Moody, Christopher J, Couch, Gavin D
Format: Article
Language:English
Subjects:
Antineoplastic Agents - chemical synthesis
Antineoplastic Agents - chemistry
Antineoplastic Agents - metabolism
Antineoplastic Agents - pharmacology
Biological Products - chemistry
Biological Products - metabolism
Biological Products - pharmacology
Humans
NAD(P)H Dehydrogenase (Quinone) - antagonists & inhibitors
NAD(P)H Dehydrogenase (Quinone) - chemistry
NAD(P)H Dehydrogenase (Quinone) - genetics
NAD(P)H Dehydrogenase (Quinone) - metabolism
Oxidation-Reduction
Prodrugs - chemical synthesis
Prodrugs - chemistry
Prodrugs - metabolism
Prodrugs - pharmacology
Quinones - chemical synthesis
Quinones - chemistry
Quinones - metabolism
Quinones - pharmacology
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Summary:The quinone reductase enzyme NAD(P)H: quinone oxidoreductase 1 (NQO1) is a ubiquitous flavoenzyme that catalyzes the two-electron reduction of quinones. This Perspective briefly reviews the structure and mechanism, physiological role, and upregulation and induction of the enzyme, but focuses on the synthesis of new heterocyclic quinones and their metabolism by recombinant human NQO1. Thus a range of indolequinones, some of which are novel analogues of mitomycin C, benzimidazolequinones, benzothiazolequinones and quinolinequinones have been prepared and evaluated, leading to detailed knowledge of the structural requirements for efficient metabolism by the enzyme. Potent mechanism-based inhibitors (suicide substrates) of NQO1 have also been developed. These indolequinones irreversibly alkylate the protein, preventing its function both in standard enzyme assays and also in cells. Some of these quinones are also potent inhibitors of growth of human pancreatic cancer cells, suggesting a potential role for such compounds as therapeutic agents.
ISSN:1477-0520
1477-0539
DOI:10.1039/b715270a