Patterson L H
Department of Pharmacy, School of Applied Sciences, De Montfort University, The Gateway, Leicester, UK.
Cancer Metastasis Rev. 1993 Jun;12(2):119-34. doi: 10.1007/BF00689805.
NAD(P)H dependent cytochrome P450's and other haemoproteins under hypoxia, mediate two-electron reduction of a wide range of structurally dissimilar N-oxides to their respective tertiary amines. Metabolic reduction can be utilised, in acute and chronic hypoxia, to convert N-oxides of DNA affinic agents to potent and persistent cytotoxins. In this respect a knowledge of N-oxide bioreduction and the importance of the cationic nature of agents that bind to DNA by intercalation can be combined to rationalise N-oxides as prodrugs of DNA binding agents. The concept is illustrated using the alkylaminoanthraquinones which are a group of cytotoxic agents with DNA binding affinity that is dependent on the cationic nature of these compounds. The actions of the alkylaminoanthraquinones involve drug intercalation into DNA (and double stranded RNA) and inhibition of both DNA and RNA polymerases and topoisomerase Type I and II. A di-N-oxide analogue of mitoxantrone, 1,4-bis([2-(dimethylamino-N-oxide)ethyl]amino)5,8-dihydroxyanthracene -9,10- dione (AQ4N) has been shown to possess no intrinsic binding affinity for DNA and has low toxicity. Yet in the absence of air AQ4N can be reduced in vitro to a DNA affinic agent with up to 1000-fold increase in cytotoxic potency. Importantly the reduction product, AQ4, is stable under oxic conditions. Studies in vivo indicate that antitumour activity of AQ4N is manifest under conditions that promote transient hypoxia and/or diminish the oxic tumour fraction. The advantage of utilising the reductive environment of hypoxic tumours to reduce N-oxides is that, unlike conventional bioreductive agents, the resulting products will remain active even if the hypoxia that led to bioactivation is transient or the active compounds, once formed, diffuse away from the hypoxic tumour regions. Furthermore, the DNA affinic nature of the active compounds should ensure their localisation in tumour tissue.
在缺氧条件下，NAD(P)H依赖的细胞色素P450和其他血红素蛋白介导多种结构不同的N-氧化物双电子还原为各自的叔胺。在急性和慢性缺氧情况下，代谢还原可用于将DNA亲和剂的N-氧化物转化为强效且持久的细胞毒素。在这方面，了解N-氧化物生物还原以及通过插入与DNA结合的试剂阳离子性质的重要性，可以结合起来将N-氧化物合理化为DNA结合剂的前药。使用烷基氨基蒽醌来说明这一概念，烷基氨基蒽醌是一组具有DNA结合亲和力的细胞毒性剂，其亲和力取决于这些化合物的阳离子性质。烷基氨基蒽醌的作用包括药物插入DNA（和双链RNA）以及抑制DNA和RNA聚合酶以及拓扑异构酶I型和II型。米托蒽醌的二-N-氧化物类似物1,4-双([2-(二甲基氨基-N-氧化物)乙基]氨基)-5,8-二羟基蒽-9,10-二酮(AQ4N)已被证明对DNA没有内在结合亲和力且毒性较低。然而，在无氧条件下，AQ4N在体外可被还原为一种DNA亲和剂，其细胞毒性效力可提高多达1000倍。重要的是，还原产物AQ4在有氧条件下是稳定的。体内研究表明，AQ4N的抗肿瘤活性在促进短暂缺氧和/或减少有氧肿瘤部分的条件下表现出来。利用缺氧肿瘤的还原环境来还原N-氧化物的优势在于，与传统的生物还原剂不同，即使导致生物活化缺氧是短暂的，或者活性化合物一旦形成就从缺氧肿瘤区域扩散出去，所产生的产物仍将保持活性。此外，活性化合物的DNA亲和性质应确保它们在肿瘤组织中的定位。
