Patterson L H, Craven M R, Fisher G R, Teesdale-Spittle P
Department of Pharmacy, School of Applied Sciences, De Montfort University, Leicester, UK.
Oncol Res. 1994;6(10-11):533-8.
The DNA binding and cytotoxicity of four intercalating agents, namely bis-alkylamino (-N(CH2)2N(CH3)2) substituted anthraquinone, anthrapyrazole and anthracene, and mono (N(CH2)2N(CH3)2) acridinone, have been compared with their respective aliphatic amine N-oxides -N(CH2)2N+(O-)(CH3)2. The results show that, unlike the intercalators, the N-oxides do not bind to DNA. Molecular modelling illustrates that the delta + nature of the intercalator alkylamino side chains in the protonated form allows for an attractive electrostatic interaction with phosphates of the DNA backbone, whereas the delta- partial charge on the N-oxide makes such an interaction not permissible; indeed, the electrostatic interaction with the DNA phosphates will be repulsive. The N-oxides show little or no cytotoxicity against V79 cells at concentrations equimolar to the IC90 (concentration that inhibits 90% of cell proliferation) of the respective intercalators. However, the cytotoxicity of anthrapyrazole 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 as bioreductive prodrugs, since they possess low aerobic toxicity but under hypoxic conditions can be metabolised to a potent cytotoxic species presumed to be a DNA-binding tertiary amine.
已将四种嵌入剂，即双烷基氨基（-N(CH2)2N(CH3)2）取代的蒽醌、蒽吡唑和蒽，以及单（N(CH2)2N(CH3)2）吖啶酮的DNA结合和细胞毒性与其各自的脂肪族胺N-氧化物-N(CH2)2N+(O-)(CH3)2进行了比较。结果表明，与嵌入剂不同，N-氧化物不与DNA结合。分子模拟表明，质子化形式的嵌入剂烷基氨基侧链的δ+性质允许与DNA主链的磷酸盐形成有吸引力的静电相互作用，而N-氧化物上的δ-部分电荷使得这种相互作用不被允许；实际上，与DNA磷酸盐的静电相互作用将是排斥性的。在与各自嵌入剂的IC90（抑制90%细胞增殖的浓度）等摩尔的浓度下，N-氧化物对V79细胞几乎没有或没有细胞毒性。然而，在存在S9肝匀浆激活系统的情况下，蒽吡唑N-氧化物对缺氧V79细胞的细胞毒性显著增强。结果表明，DNA亲和剂的N-氧化物有作为生物还原前药的潜力，因为它们具有低需氧毒性，但在缺氧条件下可代谢为一种假定为与DNA结合的叔胺的强效细胞毒性物质。
