Rates of reductive elimination of substituted nitrophenols from the (indol-3-yl)methyl position of indolequinones

Swann, E.; Moody, Christopher J.; Stratford, Michael R.L.; Patel, Kantilal B.; Naylor, Matthew A.; Vojnovic, Borivoj; Wardman, Peter; Everett, Steven A.

doi:10.1039/b101842f

Cited by 15 publications

(24 citation statements)

References 22 publications

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“…The following compounds were prepared as previously described: 5, 46 7, 46 9, 46 13, 46 15, 46 16, 47,48 18 and 19, 46 21, 46 22, 45 24-26, 49 27, 45 29, 45 31-33, 46 and 35. 46 3-Acetyl-5-methoxy-1-methylindole-4,7-dione (2).…”

Section: Methodsmentioning

confidence: 99%

Indolequinone Antitumor Agents: Correlation between Quinone Structure and Rate of Metabolism by Recombinant Human NAD(P)H:Quinone Oxidoreductase. Part 2

et al. 2001

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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. Indolequinones were selected for study on the basis of the X-ray crystal structure of the human enzyme, and were designed to probe the effect of substituents particularly at N-1. 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, and that groups larger than methyl at N-1 are clearly tolerated. Compounds with a leaving group at the 3-indolyl methyl position generally inactivated the enzyme. The toxicity toward human colon carcinoma cells with either no detectable activity (BE-WT) or high NQO1 activity (BE-NQ) was also studied in representative quinones. The most toxic compounds were those with a leaving group at the C-3 position; these compounds were 1.1-5.3-fold more toxic to the BE-NQ than the BE-WT cells.

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Section: Methodsmentioning

confidence: 99%

Indolequinone Antitumor Agents: Correlation between Quinone Structure and Rate of Metabolism by Recombinant Human NAD(P)H:Quinone Oxidoreductase. Part 2

et al. 2001

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“…Clearly both lowering the pK a of the leaving group and incorporation of a suitable radical stabilizing substituent at the indolyl carbinyl position can have a dramatic effect on rates of elimination. 80 The above studies on model drug molecules as leaving groups have defined the physico-chemical parameters for a successful indolequinone based bioreductive drug delivery strategy, although we have yet to put this into practice with "real" anticancer drug molecules. Nevertheless, some further progress has been made recently.…”

Section: Indolequinones As Prodrugs: Bioreductive Drug Deliverymentioning

confidence: 99%

Natural and synthetic quinones and their reduction by the quinone reductase enzyme NQO1: from synthetic organic chemistry to compounds with anticancer potential

2008

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The quinone reductase enzyme NAD(P)H: quinone oxidoreductase 1 (NQO1) is a ubiquitous flavoenzyme that catalyzes the two-electron reduction of quinones. This Perspective briefly reviews the structure and mechanism, physiological role, and upregulation and induction of the enzyme, but focuses on the synthesis of new heterocyclic quinones and their metabolism by recombinant human NQO1. Thus a range of indolequinones, some of which are novel analogues of mitomycin C, benzimidazolequinones, benzothiazolequinones and quinolinequinones have been prepared and evaluated, leading to detailed knowledge of the structural requirements for efficient metabolism by the enzyme. Potent mechanism-based inhibitors (suicide substrates) of NQO1 have also been developed. These indolequinones irreversibly alkylate the protein, preventing its function both in standard enzyme assays and also in cells. Some of these quinones are also potent inhibitors of growth of human pancreatic cancer cells, suggesting a potential role for such compounds as therapeutic agents.

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“…The salient feature of these ρ-values is that the highly activated DNPO had the highest absolute ρ-values, but two oxalates, TCPO and 2,6-DCPO, had the lowest values. Because the pKa values of the phenols [43,44] are the tentative indicators of their electronic nature, the pKa of the phenols forming the oxalates (Table 1) are also related to the ρ-values as shown in Fig. 4, in which the oxalates consisting of strongly acidic phenols tend to produce high absolute ρ-values except for TCPO and 2,6-DCPO.…”

Section: Dsb Enhanced Po-cl Reactions Of the Eight Oxalates And The Hmentioning

confidence: 99%

The Hammett correlation between distyrylbenzene substituents and chemiluminescence efficiency providing various ρ-values for peroxyoxalate chemiluminescence of several oxalates

Maruyama

Narita

Motoyoshiya

2013

Journal of Photochemistry and Photobiology A: Chemistry

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Peroxyoxalate chemiluminescence (PO-CL) was investigated using eight oxalates with various phenol moieties and the distyrylbenzene (DSB) fluorophores with various substituents. The ρ-values in the Hammett correlation between the substituent constants (σ p + ) of the DSBs and the singlet chemiexcitation yields (Φ S ) for the PO-CL reactions varied from -0.50 to -1.01 depending on the oxalate structure, and the reactive oxalates tended to afford the higher absolute ρ-values but with a few exceptions. Based on the CIEEL mechanism, these experimental observations suggest that the aryloxy groups still remain in the 1,2-dioxetanones (DOTs), which are the postulated high-energy intermediates, and control the electronic properties of DOTs as electron-acceptors. The LUMO energies of the DOTs calculated by the ab initio method with a B3LYP/6-31g(d) basis set reveal that the lower the DOT-LUMO energies, the higher the absolute ρ-values were provided for the corresponding oxalates, as predicted by the frontier molecular orbital (FMO) theory. Thus, the chemical species interacting with the DSBs would be not unitary and will be DOTs.2

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Rates of reductive elimination of substituted nitrophenols from the (indol-3-yl)methyl position of indolequinones

Cited by 15 publications

References 22 publications

Indolequinone Antitumor Agents: Correlation between Quinone Structure and Rate of Metabolism by Recombinant Human NAD(P)H:Quinone Oxidoreductase. Part 2

Indolequinone Antitumor Agents: Correlation between Quinone Structure and Rate of Metabolism by Recombinant Human NAD(P)H:Quinone Oxidoreductase. Part 2

Natural and synthetic quinones and their reduction by the quinone reductase enzyme NQO1: from synthetic organic chemistry to compounds with anticancer potential

The Hammett correlation between distyrylbenzene substituents and chemiluminescence efficiency providing various ρ-values for peroxyoxalate chemiluminescence of several oxalates

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