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

寻找更有效的抗癌药物的重点是开发能够杀死缺氧肿瘤的药物，这被认为是癌症化疗和放疗的一个问题。据报道，许多杂环二氮氧化物对哺乳动物和细菌细胞具有细胞毒性。毒性机制被认为涉及母体n-氧化物的单电子还原活化，这可能导致OH和O2-的产生。虽然这些试剂的作用位点尚未确定，但似乎可以合理地预测，一种能够与DNA结合并产生可扩散氧自由基的杂环二氮氧化物将影响DNA链的断裂。因此，2aminalkylphenazine 5, lO-di-N-oxide(1)被设计为在生理条件下产生可扩散氧自由基并伴随DNA链断裂。在nadh存在的情况下，非那嗪二氧化物1在有氧和厌氧条件下都能切割DNA。在厌氧条件下，随着DMSO浓度的增加，1的DNA切割活性被抑制，这表明n -氧化物利用氧产生羟基自由基。为了提高非那嗪二氮氧化物的DNA切割能力，还设计并合成了1,2 -氨基烷基- 1,5 -二羟基非那嗪二氮氧化物(2)。羟基取代基与n -氧化物的氢键可能会增加2的亲电性，导致羟基自由基的生成比1更容易。事实上，在厌氧条件下，2显示了较强的dnacleave活性。最后，在厌氧条件下有效的DNA切割活性可能使羟基吩那嗪二氮氧化物2成为能够杀死缺氧细胞的抗肿瘤药物的候选药物，这些细胞已知存在于许多人类肿瘤中作为靶细胞。

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.