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Int. J. Mol. Sci. 2014, 15(12), 23307-23331; doi:10.3390/ijms151223307

The Study of NADPH-Dependent Flavoenzyme-Catalyzed Reduction of Benzo[1,2-c]1,2,5-oxadiazole N-Oxides (Benzofuroxans)

1
Institute of Biochemistry of Vilnius University, Mokslininku 12, LT-08662 Vilnius, Lithuania
2
Institute of Bioorganic Chemistry, National Academy of Sciences of Belarus, Kuprevich 5/2, 220141 Minsk, Belarus
*
Author to whom correspondence should be addressed.
Received: 13 August 2014 / Revised: 3 December 2014 / Accepted: 4 December 2014 / Published: 15 December 2014
(This article belongs to the Section Biochemistry, Molecular and Cellular Biology)
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Abstract

The enzymatic reactivity of a series of benzo[1,2-c]1,2,5-oxadiazole N-oxides (benzofuroxans; BFXs) towards mammalian single-electron transferring NADPH:cytochrome P-450 reductase (P-450R) and two-electron (hydride) transferring NAD(P)H:quinone oxidoreductase (NQO1) was examined in this work. Since the =N+ (→O)O moiety of furoxan fragments of BFXs bears some similarity to the aromatic nitro-group, the reactivity of BFXs was compared to that of nitro-aromatic compounds (NACs) whose reduction mechanisms by these and other related flavoenzymes have been extensively investigated. The reduction of BFXs by both P-450R and NQO1 was accompanied by O2 uptake, which was much lower than the NADPH oxidation rate; except for annelated BFXs, whose reduction was followed by the production of peroxide. In order to analyze the possible quantitative structure-activity relationships (QSARs) of the enzymatic reactivity of the compounds, their electron-accepting potency and other reactivity indices were assessed by quantum mechanical methods. In P-450R-catalyzed reactions, both BFXs and NACs showed the same reactivity dependence on their electron-accepting potency which might be consistent with an “outer sphere” electron transfer mechanism. In NQO1-catalyzed two-electron (hydride) transferring reactions, BFXs acted as more efficient substrates than NACs, and the reduction efficacy of BFXs by NQO1 was in general higher than by single-electron transferring P-450R. In NQO1-catalyzed reactions, QSARs obtained showed that the reduction efficacy of BFXs, as well as that of NACs, was determined by their electron-accepting potency and could be influenced by their binding mode in the active center of NQO1 and by their global softness as their electronic characteristic. The reductive conversion of benzofuroxan by both flavoenzymes yielded the same reduction product of benzofuroxan, 2,3-diaminophenazine, with the formation of o-benzoquinone dioxime as a putative primary reductive intermediate, which undergoes a further reduction process. Overall, the data obtained show that by contrast to NACs, the flavoenzyme-catalyzed reduction of BFXs is unlikely to initiate their redox-cycling, which may argue for a minor role of the redox-cycling-type action in the cytotoxicity of BFXs. View Full-Text
Keywords: benzofuroxan; flavoenzyme; redox-cycling; bioreductive conversion; quantitative structure activity relationship; quantum mechanical calculation; DFT benzofuroxan; flavoenzyme; redox-cycling; bioreductive conversion; quantitative structure activity relationship; quantum mechanical calculation; DFT
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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Šarlauskas, J.; Misevičienė, L.; Marozienė, A.; Karvelis, L.; Stankevičiūtė, J.; Krikštopaitis, K.; Čėnas, N.; Yantsevich, A.; Laurynėnas, A.; Anusevičius, Ž. The Study of NADPH-Dependent Flavoenzyme-Catalyzed Reduction of Benzo[1,2-c]1,2,5-oxadiazole N-Oxides (Benzofuroxans). Int. J. Mol. Sci. 2014, 15, 23307-23331.

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