Oxidatively Activated DNA-Modifying Agents for Selective Cytotoxicity
Oxidatively Activated DNA-Modifying Agents for Selective Cytotoxicity
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DOI：
10.1002/cmdc.201100014
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发表时间：
2011-05-02
期刊：
影响因子：
3.4
通讯作者：
Merino, Edward J.
中科院分区：
文献类型：
--
作者：
Li, Guorui;Bell, Tiffany;Merino, Edward J.
dna修饰剂是癌症化疗治疗的重要手段，但需要对设计进行重大改进，以提高选择性，减少副作用，并使其继续广泛使用。在此，我们提出了一种新的设计策略，其中dna修饰剂含有一个可氧化的离去基和一个氮芥。这些试剂在氧化时形成强亲电试剂。通过水解测定的活化表明，氧化剂使反应活性增加了1700倍。在2'-脱氧鸟苷存在下的反应导致病变的形成。在HeLa细胞中测定的细胞毒性表明，低IC50值需要可氧化对苯二酚和氮芥片段。15种癌细胞系的细胞毒性测量表明，氧化激活的dna修饰剂具有高度选择性，因为测试的类似物在15种细胞系中只有3种的IC50值小于10 μ m；相反，顺铂对15个细胞系中的13个具有高毒性。氧化激活的dna损伤剂的选择性细胞毒性可能对肾癌细胞有用，因为786-O细胞系模型实验的IC50值为5 μ m。
DNA-modifying agents are stalwarts of chemotherapeutic cancer treatments, but require significant design improvements to improve selectivity, minimize side effects, and for their widespread use to continue. Herein we present a novel design strategy in which DNA-modifying agents contain an oxidizable leaving group and a nitrogen mustard. The agents form strong electrophiles specifically when oxidized. Activation, measured by hydrolysis, illustrates that oxidants increase reactivity 1700-fold. Reaction in the presence of 2'-deoxyguanosine leads to the formation of lesions. Cytotoxicity measured in HeLa cells showed that low IC50 values require an oxidizable hydroquinone and a nitrogen mustard fragment. Cytotoxicity measurements in 15 cancer cell lines demonstrates that oxidatively activated DNA-modifying agents are highly selective, as the analogue tested has IC50 values less than 10 mu m for only three of the 15 cell lines; in contrast, cisplatin is highly toxic to 13 of the 15 cell lines. The selective cytotoxicity of oxidatively activated DNA-damaging agents could be useful against kidney cancer cells, as the 786-O cell line model assay resulted in an IC50 value of 5 mu m.