Aromatic Nitrogen Mustard-Based Prodrugs: Activity, Selectivity, and the Mechanism of DNA Cross-Linking
Aromatic Nitrogen Mustard-Based Prodrugs: Activity, Selectivity, and the Mechanism of DNA Cross-Linking
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DOI：
10.1002/chem.201400090
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发表时间：
2014-06-10
影响因子：
4.3
通讯作者：
Peng, Xiaohua
中科院分区：
文献类型：
--
作者：
Chen, Wenbing;Han, Yanyan;Peng, Xiaohua
报道了三种新型h2o2活化芳香氮芥前药（6-8）。这些化合物含有一种DNA烷基化剂，通过不同的吸电子连接剂连接到H2O2响应触发器，因此它们对DNA不活跃，但可以被H2O2触发释放活性物质。在H2O2存在或不存在的情况下，通过测定DNA链间交联（ICL）的形成来研究这些化合物对DNA的活性和选择性。吸电子连接单元，如季铵盐(6)、羧酰胺(7)和碳酸盐基团(8)，足以使芳香氮芥失活，导致交联形成少于1.5%。然而，H2O2可以通过将提取基转化为给基来恢复效应器的活性，从而提高交联效率（约20%）。对ICL产物的稳定性和反应位点进行了测定，结果表明7和8不仅发生在嘌呤位点，也发生在嘧啶位点。我们首次分离并表征了典型核苷与芳香型氮芥之间形成的单体加合物（15），这支持了氮芥与dG、dA和dC发生反应。通过核磁共振波谱分析研究了其活化机理。体外细胞毒性实验表明，含羧酸酰胺连接体的化合物7可显著抑制GI（50）小于1 mm的各种癌细胞的生长，而含带电连接体的化合物6对所有细胞系均无明显毒性。这些数据表明，中性羧胺连接体是开发氮芥前药的首选材料。我们的研究结果表明，7是一种有效的抗癌前药，可以作为进一步开发的模型化合物。我们相信这些新颖的芳香氮芥末将激发进一步有效的应用。
Three novel H2O2-activated aromatic nitrogen mustard prodrugs (6-8) are reported. These compounds contain a DNA alkylating agent connected to a H2O2-responsive trigger by different electron-withdrawing linkers so that they are inactive towards DNA but can be triggered by H2O2 to release active species. The activity and selectivity of these compounds towards DNA were investigated by measuring DNA interstrand cross-link (ICL) formation in the presence or absence of H2O2. An electron-withdrawing linker unit, such as a quaternary ammonia salt (6), a carboxyamide (7), and a carbonate group (8), is sufficient to deactivate the aromatic nitrogen mustard resulting in less than 1.5% cross-linking formation. However, H2O2 can restore the activity of the effectors by converting a withdrawing group to a donating group, therefore increasing the cross-linking efficiency (>20%). The stability and reaction sites of the ICL products were determined, which revealed that alkylation induced by 7 and 8 not only occurred at the purine sites but also at the pyrimidine site. For the first time, we isolated and characterized the monomer adducts formed between the canonical nucleosides and the aromatic nitrogen mustard (15) which supported that nitrogen mustards reacted with dG, dA, and dC. The activation mechanism was studied by NMR spectroscopic analysis. An in vitro cytotoxicity assay demonstrated that compound 7 with a carboxyamide linker dramatically inhibited the growth of various cancer cells with a GI(50) of less than 1 mm, whereas compound 6 with a charged linker did not show any obvious toxicity in all cell lines tested. These data indicated that a neutral carboxyamide linker is preferable for developing nitrogen mustard prodrugs. Our results showed that 7 is a potent anticancer prodrug that can serve as a model compound for further development. We believe these novel aromatic nitrogen mustards will inspire further and effective applications.