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.
Highlights
The derivatives of benzo[1,2-c]1,2,5-oxadiazole N-oxide comprise an important class of pharmacologically active heterocyclic compounds, which possess antileukemic, immunosuppressive, anti-infective, antibacterial, antifungal, insecticidal, and antiparasitic activities ([1,2,3,4,5,6], and references therein)
It was found that in single-electron transferring P-450 reductase (P-450R)-catalyzed reactions, BFXs and nitroaromatic compounds (NACs) demonstrated the same dependence upon their electron-accepting potency, whereas in two-electron transferring NQO1-catalyzed reactions, BFXs acted as more efficient substrates than NACs
The results of this work show that BFXs act as relatively efficient substrates for single-electron transferring flavoenzyme P-450R as well as for two-electron transferring flavoenzyme NQO1, which are important targets for various redox-active xenobiotics and drug agents
Summary
The derivatives of benzo[1,2-c]1,2,5-oxadiazole N-oxide (benzofuroxans, BFXs) comprise an important class of pharmacologically active heterocyclic compounds, which possess antileukemic, immunosuppressive, anti-infective, antibacterial, antifungal, insecticidal, and antiparasitic (antiplasmodial and trypanocidal) activities ([1,2,3,4,5,6], and references therein). In contrast to the single-electron enzymatic reduction of NACs, their two(four)-electron enzymatic reduction results in the formation of hydroxylamines which alkylate DNA ([19] and references therein) In this context, there exist some data on the (bio)reductive transformation of BFXs, which may be important in the manifestation of their toxicity: (i) the formation of their free radicals, detected in hybrid compounds bearing BFXs as pharmacophors in the T. cruzi microsomal fraction, suggesting that. Corresponding nitroaniline derivatives by oxyhemoglobin [20]; and (iii) the reduction of benzofuroxan to o-benzoquinone dioxime and 2,3-diaminophenazine in cytosolic and microsomal fractions of rat liver [21] These data remain poorly interrelated and do not provide a quantitative insight into the mode of action of BFXs. In this study, we have examined the reactivity of a series of BFXs (Figure 1) towards single-electron transferring flavoenzyme NADPH:cytochrome P-450 reductase (P-450R; EC 1.6.2.4) and two-electron (hydride) transferring flavoenzyme NAD(P)H:quinone oxidoreductase The data show that P-450R and NQO1 can be responsible for the bio-reductive transformation of BFXs or related structure compounds bearing BFXs
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