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

Colucci, Marie A.; Reigan, Philip; Siegel, David; Chilloux, Aurelie; Ross, David; Moody, Christopher J.

doi:10.1021/jm070396q

Cited by 32 publications

(24 citation statements)

References 29 publications

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“…Comparison of the 13 C NMR spectrum of 9 to the known 5-methoxy- and 6-methoxyindolequinones22 provided clear evidence that the regioselectivity matched that reported by Murphy.…”

Section: Resultssupporting

confidence: 74%

Copper(II)‐Mediated Synthesis of Indolequinones from Bromoquinones and Enamines

Inman

Moody

2013

Eur J Org Chem

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“…Comparison of the 13 C NMR spectrum of 9 to the known 5-methoxy- and 6-methoxyindolequinones22 provided clear evidence that the regioselectivity matched that reported by Murphy.…”

Section: Resultssupporting

confidence: 74%

Copper(II)‐Mediated Synthesis of Indolequinones from Bromoquinones and Enamines

Inman

Moody

2013

Eur J Org Chem

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“…Although based on an identical indolequinone backbone as the previously reported series of NQO1 inhibitors (37, 43), the compounds reported in these studies exhibited selectivity for inhibition of NQO2. In a cell free system, rhNQO1 was only slightly inhibited by indolequinones using concentrations one order of magnitude greater than those required for complete inhibition of NQO2 (27).…”

Section: Discussionmentioning

confidence: 95%

Indolequinone Inhibitors of NRH:Quinone Oxidoreductase 2. Characterization of the Mechanism of Inhibition in both Cell-Free and Cellular Systems

et al. 2011

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We describe a series of indolequinones as efficient mechanism-based inhibitors of NRH:quinone oxidoreductase 2 (NQO2) for use either in cellular or cell-free systems. Compounds were designed to be reduced in the active site of the enzyme leading to loss of a substituted phenol leaving group and generation of a reactive iminium electrophile. Inhibition of NQO2 activity was assessed in both cell-free systems and in the human leukemia K562 cell line. Inhibition of recombinant human NQO2 by the indolequinones was NRH-dependent with kinetic parameters characteristic of mechanism-based inhibition and partition ratios as low as 2.0. Indolequinones inhibited NQO2 activity in K562 cells at nanomolar concentrations which did not inhibit NQO1 and were non-toxic to cells. Computational-based molecular modeling simulations demonstrated favorable conformations of indolequinones positioned directly above and in parallel to the isoalloxazine ring of FAD and mass spectrometry extended our previous finding of adduction of the FAD in the active site of NQO2 by an indolequinone-derived iminium electrophile to the wider series of indolequinone inhibitors. Modeling combined with biochemical testing identified key structural parameters for effective inhibition including a 5-aminoalkyamino side chain. Hydrogen bonding of the terminal amine nitrogen in the aminoalkylamino side chain was found to be critical for correct orientation of the inhibitors in the active site. These indolequinones were irreversible inhibitors and were found to be at least an order of magnitude more potent than any previously documented competitive inhibitors of NQO2 and represent the first mechanism-based inhibitors of NQO2 to be characterized in cellular systems.

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“…The IQs 2-hydroxymethyl-5-methoxy-1-methyl-3-[(4-nitrophenoxy)methyl]indole-4,7-dione (1) and 5-methoxy-1-methyl-3-[(2,4,6-trifluorophenoxy)methyl]indole-4,7-dione (2) were synthesized according to methods previously developed (Colucci et al, 2007). Recombinant human NRH:quinone oxidoreductase 2 (NQO2) was obtained from Sigma-Aldrich (St. Louis, MO).…”

Section: Methodsmentioning

confidence: 99%

Antitumor Indolequinones Induced Apoptosis in Human Pancreatic Cancer Cells via Inhibition of Thioredoxin Reductase and Activation of Redox Signaling

Yan¹,

Siegel²,

Newsome³

et al. 2012

Molecular Pharmacology

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Indolequinones (IQs) were developed as potential antitumor agents against human pancreatic cancer. IQs exhibited potent antitumor activity against the human pancreatic cancer cell line MIA PaCa-2 with growth inhibitory IC 50 values in the low nanomolar range. IQs were found to induce time-and concentrationdependent apoptosis and to be potent inhibitors of thioredoxin reductase 1 (TR1) in MIA PaCa-2 cells at concentrations equivalent to those inducing growth-inhibitory effects. The mechanism of inhibition of TR1 by the IQs was studied in detail in cell-free systems using purified enzyme. The C-terminal selenocysteine of TR1 was characterized as the primary adduction site of the IQ-derived reactive iminium using liquid chromatography-tandem mass spectrometry analysis. Inhibition of TR1 by IQs in MIA PaCa-2 cells resulted in a shift of thioredoxin-1 redox state to the oxidized form and activation of the p38/c-Jun NH 2 -terminal kinase (JNK) mitogen-activated protein kinase (MAPK) signaling pathway. Oxidized thioredoxin is known to activate apoptosis signal-regulating kinase 1, an upstream activator of p38/JNK in the MAPK signaling cascade and this was confirmed in our study providing a potential mechanism for IQ-induced apoptosis. These data describe the redox and signaling events involved in the mechanism of growth inhibition induced by novel inhibitors of TR1 in human pancreatic cancer cells.

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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

Cited by 32 publications

References 29 publications

Copper(II)‐Mediated Synthesis of Indolequinones from Bromoquinones and Enamines

Copper(II)‐Mediated Synthesis of Indolequinones from Bromoquinones and Enamines

Indolequinone Inhibitors of NRH:Quinone Oxidoreductase 2. Characterization of the Mechanism of Inhibition in both Cell-Free and Cellular Systems

Antitumor Indolequinones Induced Apoptosis in Human Pancreatic Cancer Cells via Inhibition of Thioredoxin Reductase and Activation of Redox Signaling

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