Synthesis and Evaluation of 3-Aryloxymethyl-1,2-dimethylindole-4,7-diones as Mechanism-Based Inhibitors of NAD(P)H:Quinone Oxidoreductase 1 (NQO1) Activity

NAD(P)H:quinone oxidoreductase 1 is a proposed target in pancreatic cancer. We describe the synthesis of a series of indolequinones, based on the 5- and 6-methoxy-1,2-dimethylindole-4,7-dione chromophores with a range of phenolic leaving groups at the (indol-3-yl)methyl position. The ability of thes...

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Bibliographic Details
Published in:Journal of medicinal chemistry 2007-11, Vol.50 (23), p.5780-5789
Main Authors: Colucci, Marie A, Reigan, Philip, Siegel, David, Chilloux, Aurélie, Ross, David, Moody, Christopher J
Format: Article
Language:English
Subjects:
Antineoplastic agents
Antineoplastic Agents - chemical synthesis
Antineoplastic Agents - chemistry
Antineoplastic Agents - pharmacology
Biological and medical sciences
Cell Line, Tumor
Cell Proliferation - drug effects
Drug Screening Assays, Antitumor
General aspects
Humans
Indoles - chemical synthesis
Indoles - chemistry
Indoles - pharmacology
Medical sciences
NAD(P)H Dehydrogenase (Quinone) - antagonists & inhibitors
Pancreatic Neoplasms
Pharmacology. Drug treatments
Quinones - chemical synthesis
Quinones - chemistry
Quinones - pharmacology
Structure-Activity Relationship
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Summary:NAD(P)H:quinone oxidoreductase 1 is a proposed target in pancreatic cancer. We describe the synthesis of a series of indolequinones, based on the 5- and 6-methoxy-1,2-dimethylindole-4,7-dione chromophores with a range of phenolic leaving groups at the (indol-3-yl)methyl position. The ability of these indolequinones to function as mechanism-based inhibitors of purified recombinant human NQO1 was evaluated, as was their ability to inhibit both NQO1 and cell growth in human pancreatic MIA PaCa-2 tumor cells. The inhibition of rhNQO1 was related to the pK a of the leaving group:  compounds with poorer phenolic leaving groups were poor inhibitors whereas those with more acidic leaving groups were more efficient inhibitors. These inhibition data also correlated with the inhibition NQO1 in MIA PaCa-2 cells. However, the data demonstrate that NQO1 inhibition does not correlate with growth inhibitory activity, at least in the MIA PaCa-2 cell line, suggesting that targets in addition to NQO1 need to be considered to explain the potent growth inhibitory activity of this series of indolequinones in human pancreatic cancer cells.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm070396q