Category: 192820-78-3

Dufour, Marine published the artcileMechanism-Based Inhibition of Quinone Reductase 2 (NQO2): Selectivity for NQO2 over NQO1 and Structural Basis for Flavoprotein Inhibition, Recommanded Product: 5-Methoxy-1,2-dimethyl-3-[(4-nitrophenoxy)methyl]indole-4,7-dione, the publication is ChemBioChem (2011), 12(8), 1203-1208, database is CAplus and MEDLINE.

A role for the flavoprotein NRH:quinone oxidoreductase 2 (NQO2, QR2) in human diseases such as malaria, leukemia and neurodegeneration has been proposed. In order to explore the potential of NQO2 as a therapeutic target, we have developed potent and selective mechanism-based inhibitors centered on the indolequinone pharmacophore. The compounds show remarkable selectivity for NQO2 over the closely related flavoprotein NQO1, with small structural changes defining selectivity. Biochem. studies confirmed the mechanism-based inhibition, whereas x-ray crystallog. and mass spectrometry revealed the nature of the inhibitor interaction with the protein. These indolequinones represent the first mechanism-based inhibitors of NQO2, and their novel mode of action involving alkylation of the flavin cofactor, provides significant advantages over existing competitive inhibitors in terms of potency and irreversibility, and will open new opportunities to define the role of NQO2 in disease.

ChemBioChem published new progress about 192820-78-3. 192820-78-3 belongs to indole-building-block, auxiliary class Fused/Partially Saturated Cycles,Dihydroindoles, name is 5-Methoxy-1,2-dimethyl-3-[(4-nitrophenoxy)methyl]indole-4,7-dione, and the molecular formula is C18H16N2O6, Recommanded Product: 5-Methoxy-1,2-dimethyl-3-[(4-nitrophenoxy)methyl]indole-4,7-dione.

Referemce:
https://www.nature.com/articles/s41429-020-0333-2,
Preparation of Indole Containing Building Blocks for the Regiospecific Construction of Indole Appended Pyrazoles and Pyrroles

Okubo, Ayaka published the artcileNAD(P)H dehydrogenase, quinone 1 (NQO1), protects melanin-producing cells from cytotoxicity of rhododendrol, Safety of 5-Methoxy-1,2-dimethyl-3-[(4-nitrophenoxy)methyl]indole-4,7-dione, the publication is Pigment Cell & Melanoma Research (2016), 29(3), 309-316, database is CAplus and MEDLINE.

Summary : Rhododendrol (RD) is a potent tyrosinase inhibitor that is metabolized to RD-quinone by tyrosinase, which may underlie the cytotoxicity of RD and leukoderma of the skin that may result. We have examined how forced expression of the NAD(P)H quinone dehydrogenase, quinone 1 (NQO1), a major quinone-reducing enzyme in cytosol, affects the survival of RD-treated cells. We found that treatment of the mouse melanoma cell line B16BL6 or normal human melanocytes with carnosic acid, a transcriptional inducer of the NQO1 gene, notably suppressed the cell killing effect of RD. This effect was mostly abolished by ES936, a highly specific NQO1 inhibitor. Moreover, conditional overexpression of the human NQO1 transgene in B16BL6 led to an expression-dependent increase of cell survival after RD treatment. Our results suggest that NQO1 attenuates the cytotoxicity of RD and/or its metabolites.

Pigment Cell & Melanoma Research published new progress about 192820-78-3. 192820-78-3 belongs to indole-building-block, auxiliary class Fused/Partially Saturated Cycles,Dihydroindoles, name is 5-Methoxy-1,2-dimethyl-3-[(4-nitrophenoxy)methyl]indole-4,7-dione, and the molecular formula is C18H16N2O6, Safety of 5-Methoxy-1,2-dimethyl-3-[(4-nitrophenoxy)methyl]indole-4,7-dione.

Referemce:
https://www.nature.com/articles/s41429-020-0333-2,
Preparation of Indole Containing Building Blocks for the Regiospecific Construction of Indole Appended Pyrazoles and Pyrroles

Beall, Howard D. published the artcileIndolequinone Antitumor Agents: Correlation between Quinone Structure, Rate of Metabolism by Recombinant Human NAD(P)H:Quinone Oxidoreductase, and in Vitro Cytotoxicity, Category: indole-building-block, the publication is Journal of Medicinal Chemistry (1998), 41(24), 4755-4766, database is CAplus and MEDLINE.

A series of indolequinones bearing various functional groups has been synthesized, and the effects of substituents on the metabolism of the quinones by recombinant human NAD(P)H:quinone oxidoreductase (NQO1) were studied. Thus 5-methoxyindolequinones were prepared by the Nenitzescu reaction, followed by functional group interconversions. The methoxy group was subsequently displaced by amine nucleophiles to give a series of amine-substituted quinones. Metabolism of the quinones by NQO1 revealed that, in general, compounds with electron-withdrawing groups at the indole 3-position were among the best substrates, whereas those with amine groups at the 5-position were poor substrates. Compounds with a leaving group at the 3-indolyl Me position generally inactivated the enzyme. The toxicity toward non-small-cell lung cancer cells with either high NQO1 activity (H460) or no detectable activity (H596) was also studied in representative quinones. Compounds which were good substrates for NQO1 showed the highest selectivity between the two cell lines.

Journal of Medicinal Chemistry published new progress about 192820-78-3. 192820-78-3 belongs to indole-building-block, auxiliary class Fused/Partially Saturated Cycles,Dihydroindoles, name is 5-Methoxy-1,2-dimethyl-3-[(4-nitrophenoxy)methyl]indole-4,7-dione, and the molecular formula is C18H16N2O6, Category: indole-building-block.

Referemce:
https://www.nature.com/articles/s41429-020-0333-2,
Preparation of Indole Containing Building Blocks for the Regiospecific Construction of Indole Appended Pyrazoles and Pyrroles

Everett, Steven A. published the artcileControlling the rates of reductively-activated elimination from the (indol-3-yl)methyl position of indolequinones, Product Details of C18H16N2O6, the publication is Journal of the Chemical Society, Perkin Transactions 2 (2001), 843-860, database is CAplus.

A series of substituted 3-(4-nitrophenyloxy)methylindole-4,7-diones (Q) were synthesized. The effects of substitution patterns on the indole core on rates of elimination of 4-nitrophenol as a model for drug release following fragmentation of a phenolic ether linker were studied. After reduction to either the radical anion (Q√^–) or hydroquinone (QH₂) elimination of 4-nitrophenol occurred from the (indol-3-yl)methyl position. The half-lives of Q√^– radicals at [O₂] ≈ 5 mmol dm^-3, typical of tumor hypoxia, were t_1/2 ≈ 0.3-1.8 ms, the higher values associated with higher reduction potentials. Half-lives for the autoxidation of the QH₂ were markedly longer at the same oxygen concentration (t₁/2 ≈ 8-102 min) and longer still in the presence of 4 mmol dm^-3 superoxide dismutase (t_1/2 ≈ 8-19 h). Although the indolequinones were able to eliminate 4-nitrophenol with high efficiency only Q√^– radicals of the 3-carbonyl substituted derivatives did so with sufficiently short half-lives (t_1/2 41-2 ms) to compete with electron transfer to oxygen and therefore have the potential to target the leaving group to hypoxic tissue. The hydroquinones are not sufficiently oxygen sensitive to prevent the elimination of 4-nitrophenol (t_1/2 1.5-3.5 s) even at oxygen concentrations expected in normal tissue. By incorporating electron rich substituents at the indolyl carbonyl position it is possible to control the rate of reductive fragmentation. This may prove an important factor in the design of an indolequinone-based bioreductive drug delivery system.

Journal of the Chemical Society, Perkin Transactions 2 published new progress about 192820-78-3. 192820-78-3 belongs to indole-building-block, auxiliary class Fused/Partially Saturated Cycles,Dihydroindoles, name is 5-Methoxy-1,2-dimethyl-3-[(4-nitrophenoxy)methyl]indole-4,7-dione, and the molecular formula is C18H16N2O6, Product Details of C18H16N2O6.

Referemce:
https://www.nature.com/articles/s41429-020-0333-2,
Preparation of Indole Containing Building Blocks for the Regiospecific Construction of Indole Appended Pyrazoles and Pyrroles

Swann, Elizabeth published the artcileRates of reductive elimination of substituted nitrophenols from the (indol-3-yl)methyl position of indolequinones, Recommanded Product: 5-Methoxy-1,2-dimethyl-3-[(4-nitrophenoxy)methyl]indole-4,7-dione, the publication is Journal of the Chemical Society, Perkin Transactions 2 (2001), 1340-1345, database is CAplus.

A series of indolequinones bearing substituted nitrophenols on the (indol-3-yl)methyl position (I;R¹,R²,R³,R⁴,R⁵ given: H,NO₂,H,NO₂,H; H,MeO,H,H,NO₂;H,MeO,H,NO₂,H; Me,F,H,NO₂,H; H,CHO,H,NO₂,H; etc. )was synthesized. The nitrophenol leaving groups were appropriately substituted to give a wide range (4 units) in phenolic pK_a value. The rate of reductive elimination of phenoxide anions from the (indol-3-yl)methyl position of semiquinone radicals was dependent upon this pK_a, with a decrease in 3.8 pK units shortening the half-life from 28 to 1.5 ms. Only 2,4-dinitrophenol (pK_a = 3.9) was eliminated from an unsubstituted (indol-3-yl)methyl position at a rate that would compete with reoxidation of the radical by oxygen. A nitrothiophenol leaving group was eliminated comparatively slowly and only from the hydroquinone. These studies demonstrate the dependence upon leaving group pK_a of the rate of reductive elimination from the (indol-3-yl)methyl position of indolequinones.

Journal of the Chemical Society, Perkin Transactions 2 published new progress about 192820-78-3. 192820-78-3 belongs to indole-building-block, auxiliary class Fused/Partially Saturated Cycles,Dihydroindoles, name is 5-Methoxy-1,2-dimethyl-3-[(4-nitrophenoxy)methyl]indole-4,7-dione, and the molecular formula is C13H17BO2, Recommanded Product: 5-Methoxy-1,2-dimethyl-3-[(4-nitrophenoxy)methyl]indole-4,7-dione.

Referemce:
https://www.nature.com/articles/s41429-020-0333-2,
Preparation of Indole Containing Building Blocks for the Regiospecific Construction of Indole Appended Pyrazoles and Pyrroles

Dehn, Donna L. published the artcile5-Methoxy-1,2-dimethyl-3-[(4-nitrophenoxy)methyl]indole-4,7-dione, a mechanism-based inhibitor of NAD(P)H:quinone oxidoreductase 1, exhibits activity against human pancreatic cancer in vitro and in vivo, Computed Properties of 192820-78-3, the publication is Molecular Cancer Therapeutics (2006), 5(7), 1702-1709, database is CAplus and MEDLINE.

The enzyme NAD(P)H:quinone oxidoreductase 1 (NQO1) has been found to be up-regulated in pancreatic cancer as well as many other solid tumors. A recent study showed that inhibition of NQO1 in pancreatic cancer cells using the nonselective inhibitor dicumarol suppressed the malignant phenotype. The authors suggested that inhibition of cell growth might result from an increase in intracellular superoxide production due to inhibition of NQO1. We have recently shown that NQO1 can directly scavenge superoxide and this effect may become physiol. relevant in cells containing high NQO1 levels. We therefore tested the hypothesis that 5-methoxy-1,2-dimethyl-3-[(4-nitrophenoxy)methyl]indole-4,7-dione (ES936), a specific mechanism-based inhibitor of NQO1, would be an effective agent for the treatment of pancreatic tumors. The human pancreatic tumor cell lines BxPC-3 and MIA PaCa-2 contain high levels of NQO1 activity and protein as verified by immunoblot and immunocytochem. staining of human pancreatic tumor cells. ES936 treatment inhibited NQO1 activity by >98% in MIA PaCa-2 and BxPC-3 cells. In addition, ES936 treatment induced growth inhibition [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay] in MIA PaCa-2 and BxPC-3 cells with an IC₅₀ of 108 and 365 nmol/L, resp. Treatment of MIA PaCa-2 cells with ES936 also inhibited the ability of these cells to form colonies and grow in soft agar in a dose-dependent manner. Treatment of mice carrying MIA PaCa-2 xenograft tumors with ES936 resulted in a significant difference in growth rates in ES936-treated and DMSO-treated (control) tumors. Our data did not show an increase in either intracellular superoxide production or oxygen consumption after treatment of cells with ES936, contrary to the effects seen with dicumarol. In summary, mechanism-based inhibitors of NQO1, such as ES936, may be useful therapeutic agents for the treatment of pancreatic cancer, although the underlying mechanism seems to be independent of superoxide generation.

Molecular Cancer Therapeutics published new progress about 192820-78-3. 192820-78-3 belongs to indole-building-block, auxiliary class Fused/Partially Saturated Cycles,Dihydroindoles, name is 5-Methoxy-1,2-dimethyl-3-[(4-nitrophenoxy)methyl]indole-4,7-dione, and the molecular formula is C18H16N2O6, Computed Properties of 192820-78-3.

Referemce:
https://www.nature.com/articles/s41429-020-0333-2,
Preparation of Indole Containing Building Blocks for the Regiospecific Construction of Indole Appended Pyrazoles and Pyrroles

Dehn, Donna L. published the artcileBiochemical, cytotoxic, and genotoxic effects of ES936, a mechanism-based inhibitor of NAD(P)H:quinone oxidoreductase 1, in cellular systems, Product Details of C18H16N2O6, the publication is Molecular Pharmacology (2003), 64(3), 714-720, database is CAplus and MEDLINE.

The specific involvement of NAD(P)H:quinone oxidoreductase 1 (NQO1) in the bioactivation of quinone prodrugs has been shown through the use of the inhibitor of NQO1, dicoumarol. Disadvantages of using dicoumarol to inhibit NQO1 include its lack of specificity and its competitive mechanism of inhibition. The concentration of dicoumarol required for inhibition of NQO1 varies according to the substrate under evaluation, which may lead to either false conclusions of the involvement of NQO1 or the alteration of other cellular processes. We have reported previously on the chem. and biochem. properties of ES936, a mechanism-based inhibitor of NQO1 in cell-free systems. In this study, we investigated the effects of ES936 in cellular systems. ES936 (100 nM) inhibits more than 95% of NQO1 activity within 30 min and is stable in complete media at this concentration for a min. of 2 h. The duration of inhibition is cell line-specific because a new protein must be generated for resumption of activity. ES936 abrogates the toxicity of streptonigrin, with greater effects seen in cell lines expressing higher levels of NQO1. ES936 does not inhibit other cellular reductases, nor does it alter cellular levels of acid-soluble thiols. Some evidence of DNA strand breaks was observed at the concentrations of ES936 required for the inhibition of NQO1 activity. From our studies, we propose the use of ES936 (100 nM) as a mechanism-based inhibitor of NQO1 in cellular systems and for use as a component of the routine activity assay for NQO1.

Molecular Pharmacology published new progress about 192820-78-3. 192820-78-3 belongs to indole-building-block, auxiliary class Fused/Partially Saturated Cycles,Dihydroindoles, name is 5-Methoxy-1,2-dimethyl-3-[(4-nitrophenoxy)methyl]indole-4,7-dione, and the molecular formula is C18H16N2O6, Product Details of C18H16N2O6.

Referemce:
https://www.nature.com/articles/s41429-020-0333-2,
Preparation of Indole Containing Building Blocks for the Regiospecific Construction of Indole Appended Pyrazoles and Pyrroles

Gustafson, Daniel L. published the artcileKinetics of NAD(P)H:quinone oxidoreductase I (NQO1) inhibition by mitomycin C in vitro and in vivo, Name: 5-Methoxy-1,2-dimethyl-3-[(4-nitrophenoxy)methyl]indole-4,7-dione, the publication is Journal of Pharmacology and Experimental Therapeutics (2003), 305(3), 1079-1086, database is CAplus and MEDLINE.

The bioreductive activation of the antitumor quinone mitomycin C (MMC) by NAD(P)H: quinone oxidoreductase 1 (NQO1) is complicated by the ability of MMC to also act as a mechanism-based inhibitor of NQO1 in a pH dependent manner. Inhibition of NQO1 by MMC has been studied in purified enzyme preparations and in cultured cells but has not determined in vivo. In the studies presented here, NQO1 activity was measured in mouse tissues following treatment with MMC or the potent mechanism-based human NQO1 inhibitor 5-methoxy-1,2-dimethyl-[(4-nitrophenoxy)methyl]indole-4,7-dione (ES936). NQO1 activity was significantly decreased at 1, 2, and 4 h following MMC (10 or 20 mg/kg) treatment in kidney and lung but was unchanged in brain, heart, liver, and bladder. ES936 (1 mg/kg) treatment led to a significant and much more potent inhibition of NQO1 in all murine tissues analyzed except for bladder. To extrapolate these in vivo results from mice to humans, the species-specific kinetics of NQO1 inactivation by MMC was determined in vitro using mouse, rat, and human recombinant NQO1 proteins. Results showed the inactivation kinetics of mouse and human proteins by MMC were similar. Treatment of human and murine endothelial cells with MMC or ES936 showed similar inhibition of NQO1 activity. The aforementioned results clearly demonstrate that MMC can serve as a substrate for NQO1 in vivo; however, the metabolism resulting in enzyme inactivation is possibly tissue-specific. Furthermore, the kinetic similarities for inactivation between murine and human forms of NQO1 show these results are apropos to clin. use of MMC.

Journal of Pharmacology and Experimental Therapeutics published new progress about 192820-78-3. 192820-78-3 belongs to indole-building-block, auxiliary class Fused/Partially Saturated Cycles,Dihydroindoles, name is 5-Methoxy-1,2-dimethyl-3-[(4-nitrophenoxy)methyl]indole-4,7-dione, and the molecular formula is C18H16N2O6, Name: 5-Methoxy-1,2-dimethyl-3-[(4-nitrophenoxy)methyl]indole-4,7-dione.

Referemce:
https://www.nature.com/articles/s41429-020-0333-2,
Preparation of Indole Containing Building Blocks for the Regiospecific Construction of Indole Appended Pyrazoles and Pyrroles

Yan, Chao published the artcilePotent activity of indolequinones against human pancreatic cancer: identification of thioredoxin reductase as a potential target, Computed Properties of 192820-78-3, the publication is Molecular Pharmacology (2009), 76(1), 163-172, database is CAplus and MEDLINE.

The indolequinone ES936 {5-methoxy-1,2-dimethyl-3-[(4-nitrophenoxy)methyl]indole-4,7-dione} was previously developed in our laboratory as an antitumor agent against pancreatic cancer. The objective of this study was to identify indolequinones with improved potency against pancreatic cancer and to define their mechanisms of action. Pancreatic cancer cell lines PANC-1, MIA PaCa-2, and BxPC-3 were used in in vitro assays [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium (MTT) and clonogenic assays]; indolequinones displayed potent cytotoxicity against all three cell lines, and two specific classes of indole-quinone were particularly potent agents. These indolequinones induced caspase-dependent apoptosis but no redox cycling or oxidative stress in MIA PaCa-2 and BxPC-3 cells. Selected indolequinones were also screened against the NCI-60 cell line panel and were found to be particularly effective against colon, renal, and melanoma cancer cells. A potential target of these indolequinones was identified as thioredoxin reductase. Indolequinones were found to be potent inhibitors of thioredoxin reductase activity both in pancreatic cancer cells and in cell-free systems. The mechanism of action of the indolequinones was shown to involve metabolic reduction, loss of a leaving group to generate a reactive electrophile resulting in alkylation of the selenocysteine residue in the active site of thioredoxin reductase. In vivo efficacy of the indolequinones was also tested in the MIA PaCa-2 pancreatic tumor xenograft in nude mice, and lead indolequinones demonstrated high efficacy and low toxicity. Inhibition of thioredoxin reductase represents a potential novel target in pancreatic cancer and may provide a biomarker of effect of lead indolequinones in this type of cancer.

Molecular Pharmacology published new progress about 192820-78-3. 192820-78-3 belongs to indole-building-block, auxiliary class Fused/Partially Saturated Cycles,Dihydroindoles, name is 5-Methoxy-1,2-dimethyl-3-[(4-nitrophenoxy)methyl]indole-4,7-dione, and the molecular formula is C5H5F3O2, Computed Properties of 192820-78-3.

Referemce:
https://www.nature.com/articles/s41429-020-0333-2,
Preparation of Indole Containing Building Blocks for the Regiospecific Construction of Indole Appended Pyrazoles and Pyrroles

Bian, Jinlei published the artcileDiscovery of NAD(P)H:quinone oxidoreductase 1 (NQO1) inhibitors with novel chemical scaffolds by shape-based virtual screening combined with cascade docking, Quality Control of 192820-78-3, the publication is RSC Advances (2015), 5(61), 49471-49479, database is CAplus.

A number of novel NAD(P)H:quinone oxidoreductase 1 (NQO1) inhibitors were discovered from the ChemDiv database via a simple protocol. Based on two reference NQO1 inhibitors, dicoumarol (DIC) and ES936, a shape-based similarity search and cascade docking filtering were conducted to identify new NQO1 inhibitors. Using these techniques, 43 compounds were selected, ordered, and tested. Among them, 7 compounds with novel chem. scaffolds were confirmed to be active by in vitro assays. Determination of the ability for protecting against NQO1-mediated toxicity of β-lapachone (β-lap) confirmed that compounds 8, 10 and 13 may be pharmacol. useful for probing the function of NQO1 in cells.

RSC Advances published new progress about 192820-78-3. 192820-78-3 belongs to indole-building-block, auxiliary class Fused/Partially Saturated Cycles,Dihydroindoles, name is 5-Methoxy-1,2-dimethyl-3-[(4-nitrophenoxy)methyl]indole-4,7-dione, and the molecular formula is C18H16N2O6, Quality Control of 192820-78-3.

Referemce:
https://www.nature.com/articles/s41429-020-0333-2,
Preparation of Indole Containing Building Blocks for the Regiospecific Construction of Indole Appended Pyrazoles and Pyrroles