Flavoenzyme-catalyzed single-electron reduction of nitroaromatic antiandrogens: implications for their cytotoxicity

Single- and Two-Electron Reduction of Nitroaromatic Compounds by Flavoenzymes: Mechanisms and Implications for Cytotoxicity

“…This additionally supports an "outer-sphere" reaction model because the electron selfexchange constants for ArNO 2 are by two orders of magnitude lower than those for quinones [25,26,29]. Subsequently, the linear log (k cat /K m ) vs. E 1 7 relationships were used for the estimation of unknown E 1 7 values of nitroaromatics [11][12][13]. The redox partners of P-450R, cytochromes P-450, catalyze the denitration of ArNO 2 with the formation of corresponding hydroxyl derivatives [72,73] and reverse the accumulation of the amine products of polinitrobenzene reduction, catalyzing the formation of their hydroxylamines [74].…”

“…Another factor enhancing the reactivity of ArNO 2 is an increased torsion angle of the nitro group. This, in particular, explains why NQO1 reduces the 4-nitro group of CB-1954 (13). The combined studies of the effects of dicoumarol and cibacron blue and interdependent quinone and ArNO 2 inhibition enabled us to conclude that nitroaromatics and bulky quinones bind partly outside the nicotinamide/dicoumarol binding pocket and may partly occupy adenosine/cibacron blue binding pocket [139,141].…”

“…In this aspect, the best-characterized is the energetics of first electron transfer, described by a midpoint redox potential of the ArNO 2 /ArNO 2 − • couple (E 1 , or E 1 7 at pH 7.0). Due to the instability of free radicals in aqueous media, the E 1 7 values of nitroaromatics (Table A1, Appendix A) are usually obtained from anaerobic pulse radiolysis experiments [10][11][12][13][14][15][16][17][18][19][20][21][22][23][24]. The range of E 1 7 values of ArNO 2 with biomedical interest is from −0.6 V to −0.2 V. Further in the text, all the potentials will be given with respect to NHE.…”

“…Some improvement may be expected upon the introduction of solvent matrix effects into calculations [36]. On the other hand, the E 1 7 values of ArNO 2 may be predicted from linear log (rate constant) vs. E 1 7 relationships in single-electron reduction in nitroaromatics by flavoenzymes dehydrogenases-electrontransferases or their redox partners, FeS proteins [11][12][13]. The use of the geometric average of rate constants obtained in several enzymatic systems improves the prediction accuracy.…”

“…The numbers of compounds correspond to those in Table A1 (Appendix A). (13), CB-1954 (14), , nilutamide (15), flutamide (16), and a representative of nitroCBIs, 1-(chloromethyl)-3-(5-(2-(dimethylamino-ethoxy)indol-2-carbonyl)-5-nitro-1,2-dihydro-3H-benzo[e]-indole (56). The numbers of compounds correspond to those in Table A1 (Appendix A).…”