Fully reversible redox cycling of 2,6-dimethoxy-1,4-benzoquinone induced by ascorbate.
The kinetics of cyclic redox transformation of 2,6-dimethoxy-1, 4-benzoquinone (DMOBQ)--the well-known effective anticancer agent--induced by ascorbate (AscH-) were studied in phosphate buffer, pH 7.40, at 37 degreesC using the Clark electrode and ESR techniques. The process is due to the electron transfer from AscH- to quinone (Q): Q + AscH- --> Q*- + Asc.- + H+ (1), followed by semiquinone (Q.-) oxidation: Q.- + O2 --> Q + O2.- (2). DMOBQ, taken even at submicromolar concentrations, effectively catalyzed AscH- oxidation that manifested itself by intensive oxygen consumption and an increase in the steady-state concentration of the ascorbyl radical (Asc.-). The rate of oxygen consumption, ROX, was kept almost constant for a long time. ROX was found to be proportional to the [Q][AscH-] product and not dependent on the concentrations of the individual reagents. The rate constant for reaction (1) determined from ROX and [Asc.-] was as much as 380 +/- 40 and 280 +/- 30 M-1.sec-1, respectively. When DMOBQ was mixed with the corresponding hydroquinone, QH2, in oxygen-free buffer, the ESR signal of Q.- which formed due to the equilibrium Q + QH2 left and right arrow 2Q.- + 2H+ (3) was observed. The equilibrium constant K3 of (2.6 +/- 0.4).10-5 and the change in the reduction potential, DeltaE3 = E(Q/Q.-) - E(Q.-/QH2), of -280 mV were calculated from the steady-state concentration of Q.- at pH 7.4 and 37 degrees C. From combination of DeltaE3 determined in this study with E7(Q/Q.-) reported in the literature, a value of +190 mV was calculated for the standard second one-electron reduction potential E(Q*-/QH2). The latter is lower by 270-230 mV than that for all the studied 1, 4-hydroquinones. The very beneficial combination of E(Q/Q.-) and E(Q.-/QH2) was suggested to be the basic reason for the perfect work of DMOBQ as a redox cycling agent and its pronounced anticancer activity.
Roginsky
V A
VA
Semenov Institute of Chemical Physics, Russian Academy of Sciences, ul. Kosygina 4, Moscow, 119977 Russia. rogin@cc.nifhi.ac.ru
Bruchelt
G
G
Stegmann
H B
HB
D000970:Antineoplastic Agents / Q000378:metabolism; D001205:Ascorbic Acid / Q000378:metabolism*; D016227:Benzoquinones / Q000378:metabolism*; D002384:Catalysis; D004578:Electron Spin Resonance Spectroscopy; D005609:Free Radicals; D007700:Kinetics; D010084:Oxidation-Reduction; D010101:Oxygen Consumption
D000970:Antineoplastic Agents; D016227:Benzoquinones; D005609:Free Radicals; C030511:2,6-dimethoxy-1,4-benzoquinone; D001205:Ascorbic Acid