Oxidative Denitrification of the Antitumour Drug Hydroxyguanidine

The oxidative denitrification of the antitumour agent hydroxyguanidine (HOG) has been investigated by radiolysis methods and EPR spectroscopy. The azide radical (N3˙), a model one-electron oxidant, reacts with HOG with the rate constant 5.1 × 109 dm3 mol−1 s−1 to yield the guanidino carbon-centred radical (HOG˙) which rapidly eliminates nitric oxide (image) with the concomitant formation of urea. The HOG˙ undergoes conjugation with molecular oxygen to form a peroxyl radical (HOGOO˙) with a rate constant 8.8 × 108 dm3 mol−1 s−1. The HOGOO˙ radical also eliminates nitric oxide but may act as a precurser to the peroxynitrite (ONOO−) ion. The oxidation of HOG by the dibromide radical (image) was found to release nitric oxide with a yield of 95% relative to image 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 oxidative denitrification of HOG which may contribute to the observed toxicity of the drug both in vitro and in vivo and for the oxidation of nonphysiological hydroxyguanidines to NO˙ via nitric oxide synthase-independent pathways.