OXIDATIVE DENITRIFICATION OF THE ANTITUMOR DRUG HYDROXYGUANIDINE

The oxidative denitrification of the antitumour agent hydroxyguanidine (HOG) has been investigated by radiolysis methods and EPR spectroscop y. The azide radical (N-3(.)), a model one-electron oxidant, reacts wi th HOG with the rate constant 5.1 x 10(9) dm(3) mol(-1) s(-1) to yield the guanidino carbon-centred radical (HOG(.)) which rapidly eliminate s nitric oxide (k = 3.1 x 10(3) s(-1)) with the concomitant formation of urea. The HOG(.) undergoes conjugation with molecular oxygen to for m a peroxyl radical (HOGOO(.)) with a rate constant 8.8 X 10(8) dm(3) mol(-1) s(-1). The HOGOO(.) radical also eliminates nitric oxide but m ay act as a precurser to the peroxynitrite (ONOO-) ion. The oxidation of HOG by the dibromide radical (Br-2(.-)) was found to release nitric oxide with a yield of 95% relative to Br-2(.-) as determined from the combined yields of inorganic nitrite, nitrate and a HOG/nitric oxide- adduct. This study provides a possible mechanistic basis for the oxida tive denitrification of HOG which may contribute to the observed toxic ity of the drug both in vitro and in vivo and for the oxidation of non physiological hydroxyguanidines to NO. via nitric oxide synthase-indep endent pathways. (C) 1997 Elsevier Science Inc.