Adriamycin semiquinone

SYNS ADM ADRIAMYCIN-HCl ADRIAMYCIN SEMIQUINONE ADRIBLASTINA DOXO-RUBICIN DX F.1106 14-HYDROXYDAUNO-iWCIN 14 -HYDROXYDAUNOMYCIN 14-HYDROXYDAUNORU-BICINE KW-125 NCI-C01514 NSC-123127... 

Figures. Absolute absorption spectra of adriamycin semiquinone obtained from data of Figure 2, (0) pH 1.1, ( ) pH 9.1. (Figures 2 and 3 are reproduced from reference [41] with permission.)...

Tertiary amine oxides and hydroxy la mines are also reduced by cytochromes P-450. Hydroxylamines, as well as being reduced by cytochromes P-450, are also reduced by a flavoprotein, which is part of a system, which requires NADH and includes NADH cytochrome b5 reductase and cytochrome b5. Quinones, such as the anticancer drug adriamycin (doxorubicin) and menadione, can undergo one-electron reduction catalyzed by NADPH cytochrome P-450 reductase. The semiquinone product may be oxidized back to the quinone with the concomitant production of superoxide anion radical, giving rise to redox cycling and potential cytotoxicity. This underlies the cardiac toxicity of adriamycin (see chap. 6). 

Berlin, V. and Haseltine, W.A. (1981) Reduction of adriamycin to a semiquinone-free radical by NADPH cytochrome P-450 reductase produces DNA cleavage in a reaction mediated by molecular oxygen, J. Biol. Chem. 256, 4747-4756. 

Anthracycline anti-cancer drugs, such as adriamycin, also give intense ESR spectra in anaerobic microsomal incubations [184-186], However, in these cases overlap of hyperfine lines is considerable, so that a single broad symmetric ESR line is detected, typically 4-9 G in width, with g = 2.0035. While it is extremely likely that this radical is indeed the primary semiquinone (i.e., the one-electron reduced drug), evidence to confirm the radical structure (as might perhaps be obtained from ENDOR measure-... 

Figure 2. Semiquinone-quinone difference absorption spectra for adriamycin at (o) pH 1.1 mol dm" formic acid + H2SO4) ( ) pH 9.1 (10" mol dm formate -1- borate buffer).

Mukheijee et al attempted [26,41] to quantify the observed stability of semiquinones as a function of pH, by correlating the Keq values with pK values of the species involved and their redox characteristics (Figures 6 and 7). As the details may be out of scope for this review, readers are encouraged to see our work on quinizarin and adriamycin [26,41]. 

Several quinones are used clinically in the chemotherapy of cancer [61,62]. Some examples are adriamycin (doxorubicin), daunomycin (daunorubicin), mitomycin C and more recent diaziridinyl benzoquinones and diamino anthraquinones [5]. Physiological enzyme based reduction of these quinones caused by xanthine oxidase, cytochrome P450 reductase etc.[63], leads to the formation of semiquinone and hydroquinone forms. Pulse radiolysis can generate and characterise these intermediates and products [10]. 

Clinically most successful antitumour drug, adriamycin undergoes redox cycling reactions producing also some toxic side effects. When adriamycin is reduced by one-electron reducing enzymes, the daunosamine moiety is liberated. As in Mitomycin C, it was believed that the process occurred at the semiquinone stage. 

Pulse radiolysis of aqueous solution of adriamycin under reducing conditions leads to semiquinone radicals in their various protonated forms [41,57,58,66-68]. In the acidic region, a semiquinone pK of 2.9 fit the data. Daunomycin semiquinone showed the same pK within experimental error. 

In previous papers we have shown that anthracycline adriamycin (ADM) and its derivatives are strongly adsorbed on electrode surfaces and that the two-electron redox reaction of the anthraquinone moiety occurs through its semiquinone radical intermediate even in aqueous media. In addition, we have found characteristic reduction waves of molecular oxygen catalyzed by ADM and 7-deoxyadriamycinone (7-DADMN) adsorbed on basal-plane pyrolytic graphite electrode (BPGE) surfaces this report, we... 

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