scholarly journals Reactions of Plasmodium falciparum Ferredoxin:NADP+ Oxidoreductase with Redox Cycling Xenobiotics: A Mechanistic Study

2020 ◽  
Vol 21 (9) ◽  
pp. 3234 ◽  
Author(s):  
Mindaugas Lesanavičius ◽  
Alessandro Aliverti ◽  
Jonas Šarlauskas ◽  
Narimantas Čėnas
Keyword(s):  
Plasmodium Falciparum ◽  
Redox Cycling ◽  
Single Electron ◽  
Mechanistic Study ◽  
Reductive Activation ◽  
Midpoint Potential ◽  
Quinone Reduction ◽  
Rate Limiting Step ◽  
Electron Reduction ◽  
Intrinsic Reactivity

Ferredoxin:NADP+ oxidoreductase from Plasmodium falciparum (PfFNR) catalyzes the NADPH-dependent reduction of ferredoxin (PfFd), which provides redox equivalents for the biosynthesis of isoprenoids and fatty acids in the apicoplast. Like other flavin-dependent electrontransferases, PfFNR is a potential source of free radicals of quinones and other redox cycling compounds. We report here a kinetic study of the reduction of quinones, nitroaromatic compounds and aromatic N-oxides by PfFNR. We show that all these groups of compounds are reduced in a single-electron pathway, their reactivity increasing with the increase in their single-electron reduction midpoint potential (E17). The reactivity of nitroaromatics is lower than that of quinones and aromatic N-oxides, which is in line with the differences in their electron self-exchange rate constants. Quinone reduction proceeds via a ping-pong mechanism. During the reoxidation of reduced FAD by quinones, the oxidation of FADH. to FAD is the possible rate-limiting step. The calculated electron transfer distances in the reaction of PfFNR with various electron acceptors are similar to those of Anabaena FNR, thus demonstrating their similar “intrinsic” reactivity. Ferredoxin stimulated quinone- and nitro-reductase reactions of PfFNR, evidently providing an additional reduction pathway via reduced PfFd. Based on the available data, PfFNR and possibly PfFd may play a central role in the reductive activation of quinones, nitroaromatics and aromatic N-oxides in P. falciparum, contributing to their antiplasmodial action.

scholarly journals Enzymatic single-electron reduction and aerobic cytotoxicity of tirapazamine and its 1-oxide and nor-oxide metabolites

Chemija ◽  
2018 ◽  
Vol 29 (4) ◽  
Author(s):  
Jonas Šarlauskas ◽  
Aušra Nemeikaitė-Čėnienė ◽  
Audronė Marozienė ◽  
Lina Misevičienė ◽  
Mindaugas Lesanavičius ◽  
...  
Keyword(s):  
Side Effects ◽  
Anticancer Agent ◽  
Redox Cycling ◽  
Nitroaromatic Compounds ◽  
Single Electron ◽  
Reductive Activation ◽  
Cell Nuclei ◽  
Electron Reduction ◽  
Phenylene Diamine

Aerobic cytotoxicity of 3-amino-1,2,4-benzotriazine-1,4-dioxide (tirapazamine, TPZ), a bioreductively activated hypoxia-specific anticancer agent, is responsible for TPZ side effects in chemotherapy. In order to clarify its mechanisms, we examined the aerobic cytotoxicity of TPZ and its main metabolites, 3-amino-1,2,4-benzotriazine-1-oxide and 3-amino-1,2,4-benzotriazine in murine hepatoma MH22a cells, and their reduction by NADPH:cytochrome P-450 reductase (P-450R) and ferredoxin:NADP+ reductase (FNR). Analogous studies of several quinones and nitroaromatic compounds with similar values of single-electron reduction midpoint potentials (E17) were carried out. In single-electron reduction by P-450R and FNR, the reactivity of TPZ and its monoxide was similar to that of quinones and nitroaromatics, and increased with an increase in their E17. The cytotoxicity of TPZ and its metabolites possessed a prooxidant character, because it was partly prevented by an antioxidant N,N’-diphenyl-p-phenylene diamine and desferrioxamine, and potentiated by 1,3-bis(2-chloroethyl)-1-nitrosourea. Importantly, the cytotoxicity of TPZ and, possibly, its 1-N-oxide, was much higher than that of quinones and nitroaromatics with similar values of E17 and redox cycling activities. A possible additional factor in the aerobic cytotoxicity of TPZ is its reductive activation in oxygen-poor cell nuclei, leading to the formation of DNA-damaging species similar to those forming under hypoxia.

scholarly journals Antiplasmodial Activity of Nitroaromatic Compounds: Correlation with Their Reduction Potential and Inhibitory Action on Plasmodium falciparum Glutathione Reductase

Molecules ◽  
2019 ◽  
Vol 24 (24) ◽  
pp. 4509 ◽  
Author(s):  
Audronė Marozienė ◽  
Mindaugas Lesanavičius ◽  
Elisabeth Davioud-Charvet ◽  
Alessandro Aliverti ◽  
Philippe Grellier ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Glutathione Reductase ◽  
Nitroaromatic Compounds ◽  
Vitro Activity ◽  
Antiplasmodial Activity ◽  
Single Electron ◽  
In Vitro Activity ◽  
Reductive Activation ◽  
Electron Reduction

With the aim to clarify the mechanism(s) of action of nitroaromatic compounds against the malaria parasite Plasmodium falciparum, we examined the single-electron reduction by P. falciparum ferredoxin:NADP+ oxidoreductase (PfFNR) of a series of nitrofurans and nitrobenzenes (n = 23), and their ability to inhibit P. falciparum glutathione reductase (PfGR). The reactivity of nitroaromatics in PfFNR-catalyzed reactions increased with their single-electron reduction midpoint potential (E17). Nitroaromatic compounds acted as non- or uncompetitive inhibitors towards PfGR with respect to NADPH and glutathione substrates. Using multiparameter regression analysis, we found that the in vitro activity of these compounds against P. falciparum strain FcB1 increased with their E17 values, octanol/water distribution coefficients at pH 7.0 (log D), and their activity as PfGR inhibitors. Our data demonstrate that both factors, the ease of reductive activation and the inhibition of PfGR, are important in the antiplasmodial in vitro activity of nitroaromatics. To the best of our knowledge, this is the first quantitative demonstration of this kind of relationship. No correlation between antiplasmodial activity and ability to inhibit human erythrocyte GR was detected in tested nitroaromatics. Our data suggest that the efficacy of prooxidant antiparasitic agents may be achieved through their combined action, namely inhibition of antioxidant NADPH:disulfide reductases, and the rapid reduction by single-electron transferring dehydrogenases-electrontransferases.

scholarly journals Kinetics of Flavoenzyme-Catalyzed Reduction of Tirapazamine Derivatives: Implications for Their Prooxidant Cytotoxicity

2019 ◽  
Vol 20 (18) ◽  
pp. 4602 ◽  
Author(s):  
Nemeikaitė-Čėnienė ◽  
Šarlauskas ◽  
Jonušienė ◽  
Marozienė ◽  
Misevičienė ◽  
...  
Keyword(s):  
Colon Adenocarcinoma ◽  
Human Colon ◽  
Single Electron ◽  
Reductive Activation ◽  
Midpoint Potential ◽  
Cell Compartments ◽  
Hct 116 ◽  
Electron Reduction ◽  
Hct 116 Cells ◽  
Adrenodoxin Reductase

Derivatives of tirapazamine and other heteroaromatic N-oxides (ArN→O) exhibit promising antibacterial, antiprotozoal, and tumoricidal activities. Their action is typically attributed to bioreductive activation and free radical generation. In this work, we aimed to clarify the mechanism(s) of aerobic mammalian cell cytotoxicity of ArN→O performing the parallel studies of their reactions with NADPH:cytochrome P-450 reductase (P-450R), adrenodoxin reductase/adrenodoxin (ADR/ADX), and NAD(P)H:quinone oxidoreductase (NQO1); we found that in P-450R and ADR/ADX-catalyzed single-electron reduction, the reactivity of ArN→O (n = 9) increased with their single-electron reduction midpoint potential (E17), and correlated with the reactivity of quinones. NQO1 reduced ArN→O at low rates with concomitant superoxide production. The cytotoxicity of ArN→O in murine hepatoma MH22a and human colon adenocarcinoma HCT-116 cells increased with their E17, being systematically higher than that of quinones. The cytotoxicity of both groups of compounds was prooxidant. Inhibitor of NQO1, dicoumarol, and inhibitors of cytochromes P-450 α-naphthoflavone, isoniazid and miconazole statistically significantly (p < 0.02) decreased the toxicity of ArN→O, and potentiated the cytotoxicity of quinones. One may conclude that in spite of similar enzymatic redox cycling rates, the cytotoxicity of ArN→O is higher than that of quinones. This is partly attributed to ArN→O activation by NQO1 and cytochromes P-450. A possible additional factor in the aerobic cytotoxicity of ArN→O is their reductive activation in oxygen-poor cell compartments, leading to the formation of DNA-damaging species similar to those forming under hypoxia.

scholarly journals An electron transfer driven magnetic switch: ferromagnetic exchange and spin delocalization in iron verdazyl complexes

2018 ◽  
Vol 47 (18) ◽  
pp. 6351-6360 ◽  
Author(s):  
David J. R. Brook ◽  
Connor Fleming ◽  
Dorothy Chung ◽  
Cardius Richardson ◽  
Servando Ponce ◽  
...  
Keyword(s):  
Electron Transfer ◽  
Spin Crossover ◽  
Large Change ◽  
Single Electron ◽  
Spin Multiplicity ◽  
Magnetic Switch ◽  
Ferromagnetic Exchange ◽  
Spin Delocalization ◽  
Electron Reduction

A single electron reduction of an iron bis(verdazyl) complex results in a large change in spin multiplicity resulting from a combination of spin crossover and exceptionally strong ferromagnetic exchange.

Quinone reduction and redox cycling catalysed by purified rat liver dihydrodiol/ 3α-hydroxysteroid dehydrogenase

1992 ◽  
Vol 44 (2) ◽  
pp. 341-349 ◽  
Author(s):  
Jochen Klein ◽  
Karin Post ◽  
Albrecht Seidel ◽  
Heinz Frank ◽  
Franz Oesch ◽  
...  
Keyword(s):  
Rat Liver ◽  
Hydroxysteroid Dehydrogenase ◽  
Redox Cycling ◽  
Quinone Reduction

scholarly journals Role of NAD(P)H:quinone oxidoreductase (NQO1) in apoptosis induction by aziridinylbenzoquinones RH1 and MeDZQ.

2005 ◽  
Vol 52 (4) ◽  
pp. 937-942 ◽  
Author(s):  
Ausra Nemeikaite-Ceniene ◽  
Aldona Dringeliene ◽  
Jonas Sarlauskas ◽  
Narimantas Cenas
Keyword(s):  
Regression Analysis ◽  
Redox Cycling ◽  
Apoptosis Induction ◽  
Electron Reduction ◽  
Induced Apoptosis ◽  
Phenylene Diamine

We aimed to characterize the role of NAD(P)H:quinone oxidoreductase (NQO1) in apoptosis induction by antitumour quinones RH1 (2,5-diaziridinyl-3-hydroxymethyl-6-methyl-1,4-benzoquinone) and MeDZQ (2,5-dimethyl-3,6-diaziridinyl-1,4-benzoquinone). Digitonin-permeabilized FLK cells catalyzed NADPH-dependent single- and two-electron reduction of RH1 and MeDZQ. At equitoxic concentrations, RH1 and MeDZQ induced apoptosis more efficiently than the nonalkylating duroquinone or H(2)O(2). The antioxidant N,N'-diphenyl-p-phenylene diamine, desferrioxamine, and the inhibitor of NQO1 dicumarol, protected against apoptosis induction by all compounds investigated, but to a different extent. The results of multiparameter regression analysis indicate that RH1 and MeDZQ most likely induce apoptosis via NQO1-linked formation of alkylating species but not via NQO1-linked redox cycling.

scholarly journals Combined Photoredox and Carbene Catalysis for the Synthesis of Ketones from Carboxylic Acids

2020 ◽  
Author(s):  
Anna Davies ◽  
keegan fitzpatrick ◽  
Rick Betori ◽  
Karl Scheidt
Keyword(s):  
Carboxylic Acids ◽  
Late Stage ◽  
Pharmaceutical Compounds ◽  
Single Electron ◽  
Photoredox Catalysis ◽  
Radical Coupling ◽  
Electron Reduction

Disclosed herein is the development of a novel single-electron reduction of acyl azoliums for the formation of ketones from carboxylic acids. Facile construction of the acyl azolium <i>in situ</i> followed by a radical-radical coupling was made possible using merged NHC-photoredox catalysis. The utility of this protocol in synthesis was demonstrated in the late-stage functionalization of a variety of pharmaceutical compounds.

ChemInform Abstract: PREPARATION OF β-(P′-NITROAZOXY)BENZENE AND ITS SINGLE-ELECTRON REDUCTION

1977 ◽  
Vol 8 (38) ◽  
pp. no-no
Author(s):  
V. S. SMOLYAKOV ◽  
Z. V. TODRES ◽  
A. N. USHAKOV ◽  
L. A. NEIMAN
Keyword(s):  
Single Electron ◽  
Electron Reduction

scholarly journals Aerobic Cytotoxicity of Aromatic N-Oxides: The Role of NAD(P)H:Quinone Oxidoreductase (NQO1)

2020 ◽  
Vol 21 (22) ◽  
pp. 8754
Author(s):  
Aušra Nemeikaitė-Čėnienė ◽  
Jonas Šarlauskas ◽  
Lina Misevičienė ◽  
Audronė Marozienė ◽  
Violeta Jonušienė ◽  
...  
Keyword(s):  
Human Colon ◽  
Redox Cycling ◽  
Geometric Average ◽  
Hct 116 ◽  
Radical Generation ◽  
Electron Reduction ◽  
Catalyzed Reactions ◽  
Hct 116 Cells ◽  
Derivatives Of

Derivatives of tirapazamine and other heteroaromatic N-oxides (ArN→O) exhibit tumoricidal, antibacterial, and antiprotozoal activities, which are typically attributed to bioreductive activation and free radical generation. In this work, we aimed to clarify the role of NAD(P)H:quinone oxidoreductase (NQO1) in ArN→O aerobic cytotoxicity. We synthesized 9 representatives of ArN→O with uncharacterized redox properties and examined their single-electron reduction by rat NADPH:cytochrome P-450 reductase (P-450R) and Plasmodium falciparum ferredoxin:NADP+ oxidoreductase (PfFNR), and by rat NQO1. NQO1 catalyzed both redox cycling and the formation of stable reduction products of ArN→O. The reactivity of ArN→O in NQO1-catalyzed reactions did not correlate with the geometric average of their activity towards P-450R- and PfFNR, which was taken for the parameter of their redox cycling efficacy. The cytotoxicity of compounds in murine hepatoma MH22a cells was decreased by antioxidants and the inhibitor of NQO1, dicoumarol. The multiparameter regression analysis of the data of this and a previous study (DOI: 10.3390/ijms20184602) shows that the cytotoxicity of ArN→O (n = 18) in MH22a and human colon carcinoma HCT-116 cells increases with the geometric average of their reactivity towards P-450R and PfFNR, and with their reactivity towards NQO1. These data demonstrate that NQO1 is a potentially important target of action of heteroaromatic N-oxides.

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