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首页> 外文期刊>Anti-Cancer Drug Design >Nitracrine N-oxides: effects of variations in the nature of the side chain N-oxide on hypoxia-selective cytotoxicity.
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Nitracrine N-oxides: effects of variations in the nature of the side chain N-oxide on hypoxia-selective cytotoxicity.

机译：硝氮N-氧化物：侧链N-氧化物的性质变化对缺氧选择性细胞毒性的影响。

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The tertiary amine N-oxide (nitracrine-N-oxide, 1b) of the 1-nitroacridine nitracrine is a bis-bioreductive agent showing very high hypoxic selectivity (approximately 1000-fold) against tumour cells in culture, but only modest activity against the hypoxic subfraction of tumours in vivo. Because the hypoxic selectivity of 1b was considered to depend significantly on the rate of enzyme-mediated reduction of the N-oxide group, this paper reports the preparation and evaluation of a series of analogues in which the environment of this group was modified. Three analogues contained more weakly basic N-oxides, while two others had varying degrees of steric bulk around the N-oxide. In all but one case (an aromatic N-oxide), the N-oxides were much less cytotoxic (10- to 300-fold) than the corresponding tertiary amines towards AA8 Chinese hamster cells under aerobic conditions. Both the N-oxides and the corresponding amines were more cytotoxic to an ERCC-1 mutant defective in nucleotide excision repair, indicating that DNA alkylation was the cytotoxic event. However, there was no apparent correlation of these parameters with structure. All of the aliphatic N-oxides, with the exception of the aromatic N-oxide example, showed substantial (70- to 800-fold) hypoxic selectivity against AA8 cells in a clonogenic assay. While the weakly basic derivatives were the least selective, there was no apparent relationship between hypoxic selectivity and the steric environment of the N-oxide. Selectivity for hypoxic cells in culture is shown to depend on the hypoxic selectivity of the corresponding tertiary amine (reflecting O2-inhibitable reduction of the 1-nitro group) and the differential in aerobic toxicity between amine and N-oxide (a measure of the potential toxicity increase achievable by reducing the N-oxide). Four analogues whose structures fairly represented the range of steric and electronic modifications of the N-oxide site were evaluated against the hypoxic subfraction of cells in KHT tumours in vivo, but were inactive. These results suggest that either such modifications do not exert significant effects on N-oxide reduction, or that the rate of such reduction is not a factor limiting the in vivo activity of the parent analogue 1b.
机译：1-硝基ac啶硝nitr的叔胺N-氧化物（nitracrine-N-oxide，1b）是一种双生物还原剂，对培养中的肿瘤细胞表现出很高的低氧选择性（约1000倍），但对体内低氧分馏肿瘤。因为1b的低氧选择性被认为主要取决于酶介导的N-氧化物基团还原的速率，所以本文报道了一系列修饰该基团环境的类似物的制备和评价。三个类似物含有更弱的碱性N-氧化物，而另两个类似物在N-氧化物周围具有不同程度的空间体积。除了一种情况（芳香族N-氧化物）外，在有氧条件下，N-氧化物对AA8中国仓鼠细胞的细胞毒性要比相应的叔胺低得多（10-300倍）。 N-氧化物和相应的胺对核苷酸切除修复中有缺陷的ERCC-1突变体均具有更高的细胞毒性，表明DNA烷基化是细胞毒性事件。但是，这些参数与结构没有明显的相关性。除了芳香族N-氧化物实例外，所有其他脂肪族N-氧化物在克隆形成试验中均显示出对AA8细胞的显着（70-800倍）低氧选择性。尽管弱碱性衍生物的选择性最低，但低氧选择性与N-氧化物的空间环境之间没有明显的关系。显示对培养物中低氧细胞的选择性取决于相应的叔胺的低氧选择性（反映O2抑制性的1-硝基还原）和胺与N-氧化物之间有氧毒性的差异（潜在电位的量度）通过减少N-氧化物可达到增加毒性的目的。针对体内KHT肿瘤中细胞的低氧亚组分，评估了四个结构类似地代表N-氧化物位点的空间和电子修饰范围的类似物，但它们没有活性。这些结果表明，这种修饰对N-氧化物的还原没有显着影响，或者这种还原的速率不是限制母体类似物1b的体内活性的因素。

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