Reactions of a putative metabolite of the model antitumor drug 2-(4-aminophenyl)benzothiazole with purines and pyrimidines

Derivatives of 2-(4-aminophenyl)benzothiazole, 1, are being investigated as antitumor drugs, and for other medicinal applications. Although drug development has proceeded rapidly, little is known about the basis for the activity of these drugs. We have previously shown that the putative N-acetoxy metabolite of 1, 8, decomposes in water to generate a long-lived nitrenium ion, 11 (530 ns at room temperature). The kinetics of reaction of 8 with monomeric purines and the pyrimidine cytosine in aqueous solution are consistent with trapping of 11 after rate limiting ionization of 8. This is equivalent to the behavior of similar metabolites of carcinogenic polycyclic arylamines that have also been shown to react with deoxyribonucleic acid bases via a nitrenium ion mechanism. Selectivities of 11 and the nitrenium ion 13, derived from the carcinogen 4-aminobiphenyl, for individual purines and pyrimidines are comparable, with both ions showing a marked preference for reaction with 2′-deoxyguanosine and xanthosine, and much lower selectivity for inosine, adenosine, and the pyrimidine cytosine (C). Products of the reactions of the two nitrenium ions with the individual purines are similar, although there are some notable differences. The product of the reaction of 11 with C is similar to the product of the reaction of N-acetoxy-3,5-dimethylaniline with 2′-deoxycytidine (d-C). These results indicate that 11 is not unique among arylnitrenium ions in its reactions with deoxyribonucleic acid bases. The basis for selective antitumor activity of 1 and its derivatives is not due to an unusual property of the nitrenium ion. Copyright © 2011 John Wiley & Sons, Ltd.