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

吩嗪二氮氧化物作为新型羟基自由基供体的研究

• 批准号: 12672169
• 负责人: FUKUHARA Kiyoshi
• 金额: $ 2.18万
• 依托单位: National Institute of Health Sciences
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2000
• 资助国家: 日本
• 起止时间: 2000 至 2001
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-12672169/
• 关键词: phenazine; N-oxide; hydroxyl radical; cancer; DNA damage

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.

对更有效的抗癌剂的研究集中于开发能够杀死缺氧肿瘤的药物，缺氧肿瘤被认为是癌症的化疗和放疗的问题。据报道，许多杂环二-N-氧化物对寄生虫和细菌细胞表现出细胞毒性。其毒性机制可能与母体N-氧化物的单电子还原活化有关，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期，能够与DNA结合并产生可扩散氧自由基的杂环二-N-氧化物将影响DNA链断裂。因此，2氨基烷基吩嗪5，10-二-N-氧化物（1）被设计为在生理条件下产生可扩散的氧自由基并伴随DNA链断裂。在NADH存在下，吩嗪二氮氧化物1在有氧和厌氧条件下切割DNA。在厌氧条件下，随着DMSO浓度的增加，1的DNA切割活性被淬灭，这表明通过利用N-氧化物中的氧产生羟基自由基。为了提高吩嗪二N-氧化物的DNA切割能力，还设计合成了1，2-氨烷基-1，5-二羟基吩嗪二N-氧化物（2）。羟基取代基与N-氧化物的氢键结合可能增加了2的亲电性，使其比1更容易产生羟基自由基。事实上，2在厌氧条件下表现出很强的DNA切割活性。最后，在厌氧条件下有效的DNA切割活性可能使羟基吩嗪二-N-氧化物2成为能够杀死缺氧细胞的抗肿瘤药物的候选者。已知其作为靶细胞存在于许多人类肿瘤中。

项目成果

K.Fukuhara, I Nakanishi, et al.: "Enhanced radical scavenging activity of a planar catechin analogue"J. Am. Chem. Soc.. 124(In press). (2002)

K.Fukuhara、I Nakanishi 等人：“平面儿茶素类似物的增强自由基清除活性”J.

S. Ohnishi: "Oxidative DNA damage by a metabolite of carcinogenic 1-nitropyrene"Biochem. Biophy. Res. Comm. 280. 48-52 (2001)

S. Ohnishi：“致癌 1-硝基芘代谢物造成的氧化 DNA 损伤”Biochem。

K. Fukuhara: "Electrochemical studies of quinone and nitroarene in generation and quenching of superoxide"Environ. Mutagen Res. 22. 155-162 (2000)

K. Fukuhara：“醌和硝基芳烃在超氧化物的产生和猝灭中的电化学研究”环境。

A. Matsuoka: "Resveratrol, a naturally occurring polyphenol, induces sister chromated exchanges in a Chinese hamster lung (CHL) cell line"Mutation Research. 494. 107-113 (2001)

A. Matsuoka：“白藜芦醇是一种天然存在的多酚，可在中国仓鼠肺 (CHL) 细胞系中诱导姐妹铬酸盐交换”突变研究。

K. Fukuhara: "Photochemical generation of nitric oxide from 6-nitroazabenzo[a]pyrene"J. Am. Chem. & Soc.. 123. 8662-8666 (2001)

K. Fukuhara：“6-硝基氮杂苯并[a]芘光化学生成一氧化氮”J。