ALIPHATIC AMINE N-OXIDES OF DNA-BINDING AGENTS AS BIOREDUCTIVE DRUGS

The DNA binding and cytotoxicity of four intercalating agents, namely bis-alkylamino (-N(CH2)(2)N(CH3)(2)) substituted anthraquinone, anthra pyrazole and anthracene, and mono (N(CH2)(2)N(CH3)(2)) acridinone, hav e been compared with their respective aliphatic amine N-oxides -N(CH2N +(O-)(CH3)(2). The results show that, unlike the intercalators, the N- oxides do not bind to DNA. Molecular modelling illustrates that the de lta+ nature of the intercalator alkylamino side chains in the protonat ed form allows for an attractive electrostatic interaction with phosph ates of the DNA backbone, whereas the delta+ partial charge on the N-o xide makes such an interaction not permissible; indeed, the electrosta tic interaction with the DNA phosphates will be repulsive. The N-oxide s show little or no cytotoxicity against V79 cells at concentrations e quimolar to the IC90 (concentration that inhibits 90% of cell prolifer ation) of the respective intercalators. However, the cytotoxicity of a nthrapyrazole N-oxide against hypoxic V79 cells in the presence of an activating system of S9 liver fraction was enhanced significantly. The results indicate that N-oxides of DNA-affinic agents have potential a s bioreductive prodrugs, since they possess low aerobic toxicity but u nder hypoxic conditions can be metabolised to a potent cytotoxic speci es presumed to be a DNA-binding tertiary amine.