| Indolequinone antitumour agents: correlation between quinone structure and rate of metabolism by recombinant human NAD(P)H:quinone oxidoreductase. | |
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MedLine Citation:
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PMID: 17571194 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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A series of indolequinones bearing a range of substituents at the (indol-2-yl)methyl position has been synthesized. The ability of these indolequinones to act as substrates for recombinant human NAD(P)H:quinone oxidoreductase (NQO1), a two-electron reductase upregulated in tumour cells, was determined, along with their toxicity to an isogenic tumour cell line pair that is differentiated as either NQO1-expressing cells (BE-NQ) or NQO1-null cells (BE-WT). Overall, the 2-substituted indolequinones were relatively poor substrates for NQO1. Hydroxymethyl groups at C-2 led to higher rates of reduction, a finding that was observed previously with 3-hydroxymethylated indolequinones. Predictably, the best substrate had an electron-withdrawing ester group at the indole-2-position. The indolequinones were generally non-toxic to both cell lines with the exception of those quinones that had methylaziridine groups at the indole-5-position. These compounds could form DNA cross-links when activated by reduction and were up to 3-fold more toxic to the BE-NQ cells than the BE-WT cells. |
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Authors:
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Jeffery J Newsome; Elizabeth Swann; Mary Hassani; Kurtis C Bray; Alexandra M Z Slawin; Howard D Beall; Christopher J Moody |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't Date: 2007-04-20 |
Journal Detail:
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Title: Organic & biomolecular chemistry Volume: 5 ISSN: 1477-0520 ISO Abbreviation: Org. Biomol. Chem. Publication Date: 2007 May |
Date Detail:
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Created Date: 2007-06-15 Completed Date: 2007-08-08 Revised Date: 2007-11-15 |
Medline Journal Info:
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Nlm Unique ID: 101154995 Medline TA: Org Biomol Chem Country: England |
Other Details:
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Languages: eng Pagination: 1629-40 Citation Subset: IM |
Affiliation:
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Department of Chemistry, University of Exeter, Stocker Road, Exeter, UK EX4 4QD. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Antineoplastic Agents
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chemical synthesis*,
pharmacology Cell Line, Tumor Cross-Linking Reagents / pharmacology Crystallography, X-Ray DNA / chemistry Drug Screening Assays, Antitumor Electrons Gene Expression Regulation, Neoplastic* Humans Indolequinones / pharmacology* Models, Chemical Molecular Conformation NAD(P)H Dehydrogenase (Quinone) / metabolism* Oxidation-Reduction Quinones / chemistry |
| Grant Support | |
ID/Acronym/Agency:
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P20 RR17670/RR/NCRR NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Antineoplastic Agents; 0/Cross-Linking Reagents; 0/Indolequinones; 0/Quinones; 9007-49-2/DNA; EC 1.6.5.2/NAD(P)H Dehydrogenase (Quinone) |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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