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首页> 外文期刊>European Journal of Medicinal Chemistry: Chimie Therapeutique >Structural modifications on the phenazine N,N'-dioxide-scaffold looking for new selective hypoxic cytotoxins.
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Structural modifications on the phenazine N,N'-dioxide-scaffold looking for new selective hypoxic cytotoxins.

机译：吩嗪N，N'二氧化碳 - 支架寻找新选择性缺氧细胞毒素的结构修饰。

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摘要

We have identified phenazine 5,10-dioxides as prodrugs for antitumour therapy that undergo hypoxic-selective bioreduction to form cytotoxic species. Here, we investigated some structural modifications in order to find new selective hypoxic cytotoxins and to establish the structural requirements for adequate activity. Three different chemical-series were prepared and the clonogenic survival of V79 cells on aerobic and anaerobic conditions was determined. Electrochemical- and DNA-interaction studies were done for the most relevant derivatives. The new fluoro-derivative 7-fluoro-2-aminophenazine 5,10-dioxide displayed selective toxicity towards hypoxic V79 cells having adequate hypoxic cytotoxicity ratio (HCR=6.8) and being the most potent hypoxic cytotoxins (P=2.5 muM) described for this family of bioreductive agents. The reduction potential of the N-oxide moiety in this new fluoro-derivative was in the range for adequate bioreduction property. According to the fluorescence studies, the DNA-interaction mechanism was especially operative in the phenazine drugs more than in the corresponding prodrugs, phenazine dioxides.
机译：我们已经将苯嗪5,10-二氧化氧化物作为抗肿瘤治疗的前药，其经历缺氧选择性生物测定以形成细胞毒性物质。在这里，我们研究了一些结构修饰，以寻找新的选择性缺氧细胞毒素，并建立足够的活动的结构要求。确定了三种不同的化学系列，测定了V79细胞对有氧和厌氧条件的克隆致杀菌存活。为最相关的衍生物进行电化学和DNA相互作用研究。新的氟代衍生物7-氟-2-氨基噻嗪5,10-二氧化氧化物显示出具有足够缺氧细胞毒性比（HCR = 6.8）的缺氧V79细胞的选择性毒性（HCR = 6.8），并且是为此描述的最有效的缺氧细胞毒素（P = 2.5毫米）生物科家族。在这种新的氟衍生物中的N-氧化物部分的降低电位在足够的生物诱导性质的范围内。根据荧光研究，DNA - 相互作用机理特别是在相应的前药，吩嗪二氧化物中的苯吡啶药中的尤其均匀。

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