scholarly journals QSARs in prooxidant mammalian cell cytotoxicity of nitroaromatic compounds: the roles of compound lipophilicity and cytochrome P-450- and DT-diaphorase-catalyzed reactions

Chemija ◽  
2020 ◽  
Vol 31 (3) ◽  
Author(s):  
Aušra Nemeikaitė-Čėnienė ◽  
Jonas Šarlauskas ◽  
Violeta Jonušienė ◽  
Lina Misevičienė ◽  
Audronė Marozienė ◽  
...  
Keyword(s):  
Mammalian Cell ◽  
Water Distribution ◽  
Reduction Rate ◽  
Human Colon ◽  
Nitroaromatic Compounds ◽  
Single Electron ◽  
Cell Cytotoxicity ◽  
Electron Reduction ◽  
Adrenodoxin Reductase ◽  
Dt Diaphorase

Frequently, the aerobic mammalian cell cytotoxicity of nitroaromatic compounds (ArNO2) increases with their single-electron reduction potential (E17), thus reflecting the relationship between their enzymatic single-electron reduction rate and E17. This shows that the main factor of ArNO2 cytotoxicity is redox cycling and oxidative stress. In this work, we found that the reactivity of a series of nitrobenzenes, nitrofurans and nitrothiophenes towards single-electron transferring NADPH:cytochrome P-450 reductase and adrenodoxin reductase/adrenodoxin increases with their E17. However, their cytotoxicity in mouse hepatoma MH22a and human colon carcinoma HCT-116 cells exhibited a poorly expressed dependence on E17. The correlations were significantly improved after the introduction of compound octanol/water distribution coefficient at pH 7.0 (log D) as a second variable. This shows that the lipophilicity of ArNO2 enhances their cytotoxicity. The inhibitors of cytochromes P-450, α-naphthoflavone, isoniazid and miconazole, and an inhibitor of DT-diaphorase, dicoumarol, in most cases decreased the cytotoxicity of several randomly chosen compounds. This shows that the observed cytotoxicity vs E17 relationships in fact reflect the superposition of several cytotoxicity mechanisms.

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 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 Reduction of nitroaromatic compounds by NAD(P)H:quinone oxidoreductase (NQO1): the role of electron-accepting potency and structural parameters in the substrate specificity.

2006 ◽  
Vol 53 (3) ◽  
pp. 569-576 ◽  
Author(s):  
Lina Miseviciene ◽  
Zilvinas Anusevicius ◽  
Jonas Sarlauskas ◽  
Narimantas Cenas
Keyword(s):  
Active Center ◽  
Reduction Potential ◽  
Structural Parameters ◽  
Nitroaromatic Compounds ◽  
Electronic Coupling ◽  
Quinone Binding ◽  
Lower Reactivity ◽  
Electron Reduction ◽  
Dt Diaphorase

We aimed to elucidate the role of electronic and structural parameters of nitroaromatic compounds in their two-electron reduction by NAD(P)H:quinone oxidoreductase (NQO1, DT-diaphorase, EC 1.6.99.2). The multiparameter regression analysis shows that the reactivity of nitroaromatic compounds (n=38) increases with an increase in their single-electron reduction potential and the torsion angle between nitrogroup(s) and the aromatic ring. The binding efficiency of nitroaromatics in the active center of NQO1 exerted a less evident role in their reactivity. The reduction of nitroaromatics is characterized by more positive entropies of activation than the reduction of quinones. This points to a less efficient electronic coupling of nitroaromatics with the reduced isoalloxazine ring of FAD, and may explain their lower reactivity as compared to quinones. Another important but poorly understood factor enhancing the reactivity of nitroaromatics is their ability to bind at the dicumarol/quinone binding site in the active center of NQO1.

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 Redox properties and prooxidant cytotoxicity of a neuroleptic agent 6,7-dinitrodihydroquinoxaline-2,3-dione (DNQX).

2013 ◽  
Vol 60 (2) ◽  
Author(s):  
Jonas Šarlauskas ◽  
Aušra Nemeikaitė-Čėnienė ◽  
Lina Misevičienė ◽  
Kastis Krikštopaitis ◽  
Žilvinas Anusevičius ◽  
...  
Keyword(s):  
Electrochemical Reduction ◽  
Bovine Leukemia Virus ◽  
Reduction Potential ◽  
Leukemia Virus ◽  
Redox Properties ◽  
Single Electron ◽  
Reduction Peak ◽  
Neuroleptic Agent ◽  
Electron Reduction ◽  
Dt Diaphorase

In order to characterize the possible mechanism(s) of cytotoxicity of a neuroleptic agent 6,7-dinitrodihydroquinoxaline-2,3-dione (DNQX) we examined the redox properties of DNQX, and its mononitro- (NQX) and denitro- (QX) derivatives. The irreversible electrochemical reduction of the nitro groups of DNQX was characterized by the reduction peak potentials (Ep,7) of -0.43 V and -0.72 V vs. Ag/AgCl at pH 7.0, whereas NQX was reduced at Ep,7 = -0.67 V. The reactivities of DNQX and NQX towards the single-electron transferring enzymes NADPH:cytochrome P-450 reductase and NADPH:adrenodoxin reductase/adrenodoxin complex were similar to those of model nitrobenzenes with the single-electron reduction potential (E¹₇) values of -0.29 V - -0.42 V. DNQX and NQX also acted as substrates for two-electron transferring mammalian NAD(P)H:quinone oxidoreductase (DT-diaphorase). The cytotoxicity of DNQX in bovine leukemia virus-transformed lamb kidney fibroblasts (line FLK) was prevented by antioxidants and an inhibitor of NQO1, dicoumarol, and was enhanced by the prooxidant alkylating agent 1,3-bis(2-chloromethyl)-1-nitrosourea. A comparison with model nitrobenzene compounds shows that the cytotoxicity of DNQX and NQX reasonably agrees with the ease of their electrochemical reduction, and/or their reactivities towards the used enzymatic single-electron reducing systems. Thus, our data imply that the cytotoxicity of DNQX in FLK cells is exerted mainly through oxidative stress.

Mammalian cell cytotoxicity and genotoxicity analysis of drinking water disinfection by-products

2002 ◽  
Vol 40 (2) ◽  
pp. 134-142 ◽  
Author(s):  
Michael J. Plewa ◽  
Yahya Kargalioglu ◽  
Danielle Vankerk ◽  
Roger A. Minear ◽  
Elizabeth D. Wagner
Keyword(s):  
Drinking Water ◽  
Mammalian Cell ◽  
Water Disinfection ◽  
Cell Cytotoxicity ◽  
Drinking Water Disinfection ◽  
By Products

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.

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
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