Indolequinone antitumour agents: correlation between quinone structure and rate of metabolism by recombinant human NAD(P)H:quinone oxidoreductase.
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.
Newsome
Jeffery J
JJ
Department of Chemistry, University of Exeter, Stocker Road, Exeter, UK EX4 4QD.
Swann
Elizabeth
E
Hassani
Mary
M
Bray
Kurtis C
KC
Slawin
Alexandra M Z
AM
Beall
Howard D
HD
Moody
Christopher J
CJ
D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D045744:Cell Line, Tumor; D003432:Cross-Linking Reagents / Q000494:pharmacology; D018360:Crystallography, X-Ray; D004247:DNA / Q000737:chemistry; D004354:Drug Screening Assays, Antitumor; D004583:Electrons; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D045563:Indolequinones / Q000494:pharmacology*; D008956:Models, Chemical; D008968:Molecular Conformation; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000378:metabolism*; D010084:Oxidation-Reduction; D011809:Quinones / Q000737:chemistry
D000970:Antineoplastic Agents; D003432:Cross-Linking Reagents; D045563:Indolequinones; D011809:Quinones; D004247:DNA; D016660:NAD(P)H Dehydrogenase (Quinone)