Acid-catalyzed oxidation of the anticancer agent mitoxantrone by nitrite ions

KJ Reszka and CF Chignell

Laboratory of Molecular Biophysics, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina 22709, USA. reszka@niehs.nih.gov

Mitoxantrone (1,4-dihydroxy-5,8-bis[2-[(2- hydroxyethyl)amino]ethyl]amino-9,10-anth rac enedione; MXH2) is a novel anticancer agent that is useful in the treatment of leukemia and breast cancer. In contrast to other anthracenedione-based agents, this drug causes fewer side effects, mainly because it is resistant to metabolic reduction. We investigated the interaction between MXH2 and inorganic nitrite (NO2-) in aqueous solutions and found that this drug undergoes acid-catalyzed oxidation by nitrite. The rate of this reaction measured versus [NaNO2] at constant pH or versus pH at constant [NaNO2] was found to be directly proportional to the actual HNO2 concentration, indicating HNO2 to be the major oxidizing species. Involvement of .NO and/or NO2. radicals as minor oxidants is suggested based on the dependence of the rate of oxidation on the presence of air. Spectrophotometric and electron paramagnetic resonance analyses indicate that early products of the reaction are identical to those generated by oxidation of MXH2 by a horseradish peroxidase/hydrogen peroxide system. The major product is hexahydronaphtho[2,3- f]quinoxaline-7,12-dione, which is formed by intramolecular cyclization of one alkylamino side chain in the oxidized, diiminoquinone MX(N) form of the drug. This study shows that MXH2 effectively scavenges HNO2 and possibly other nitrogen oxides. Because these reactive forms of nitrogen may be present in vivo, this property of the drug may be relevant to its biological or perhaps anticancer activities.

Volume 50, Issue 6, pp. 1612-1618, 12/01/1996
Copyright © 1996 by American Society for Pharmacology and Experimental Therapeutics