Studies of Phenazine di N-Oxides as a New Type of Hydroxy Radical Donor

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The search for more effective anticancer agents has focus to the development of drugs capable of killing hypoxic tumors, which are considered to pose a problem for both chemotherapy and radiotherapy of cancer. A number of heterocyclic di-N-oxides have been reported to exhibit cytotoxity toward mammarian and bacterial cells. The mechenism of toxicity has been suggested to involve one-electron-reductive activation of the parent N-oxides, which could result in the production of OH and O2-. While the locus of action of these agents has not been established, it seemed reasonable to anticipate that a heterocyclic di-N-oxide capable of binding to DNA and producing diffusible oxygen radicals would effect DNA strand scission. Accordingly, 2aminoalkylphenazine 5, lO-di-N-oxide(1) was designed to produce diffusible oxygen radicals and concomitant DNA strand scission under physiological conditions. In the presence ofNADH, phenazine di-Noxide 1 cleaved DNA in both aerobic and anaerobic conditions. Under anaerobic conditions, the DNA cleaving activities of 1 were quenched with increasing DMSO concentrations, suggesting the generation of hydroxyl radical by taking advantage of oxygen in N-oxide. In order to improve the DNA cleaving ability of phenazine di-N-oxide 1, 2-aminoalkyl-1, 5-dihydroxylphenazine di-N-oxide (2) was also designed and synthesized. The hydrogen binding of hydroxyl substituent with N-oxide might increase the electrophilic nature of 2, resulting the generation of hydroxyl radical with greater facility than 1.In fact, the strong DNAcleaving activity was shown by 2 under anaerobic condition.Finally, the efficient DNA cleaving activity under anaerobic conditions might enable hydroxylphenazine di-N-oxide 2 to be candidate for antitumor agents capable for killing the hypoxic cells, which are known to be present in many human tumors as target cells.