UV-Induced DNA Interstrand Cross-Linking and Direct Strand Breaks from a New Type of Binitroimidazole Analogue
UV-Induced DNA Interstrand Cross-Linking and Direct Strand Breaks from a New Type of Binitroimidazole Analogue
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DOI：
10.1021/tx500522r
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发表时间：
2015-05-01
影响因子：
4.1
通讯作者：
Peng, Xiaohua
中科院分区：
文献类型：
--
作者：
Han, Yanyan;Chen, Wenbing;Peng, Xiaohua
合成了四种新型光活化双硝基咪唑前药。这些物质在紫外线照射下产生DNA链间交联（ICLs）和直接链断裂（DSB），而在没有紫外线照射的情况下没有或很少观察到DNA ICLs和DSB。虽然这四个分子（1-4）含有相同的双硝基咪唑片段，但它们具有四个不同的离去基，这导致它们产生不同的DNA损伤量。以氮芥为离去基的化合物4的ICL产量最高。令人惊讶的是，没有烷基化官能团的化合物1-3也诱导了DNA ICL的形成，尽管它们的产率较低，这表明紫外线照射1-3释放的双硝基咪唑片段能够交联DNA。经1.0 M哌啶在90℃下处理，这些化合物诱导的DNA交联产物被完全破坏（导致dG位点的裂解），这表明DNA交联主要通过dG的烷基化发生。我们提出了烷基化剂从这些化合物中释放的可能机制。HRMS和NMR分析证实，紫外辐照产生游离氮芥。自由基陷阱（TEMPO）抑制DNA ICL和DSB的形成，表明自由基参与了3和4与DNA的光反应。基于这些数据，我们提出化合物1-4的紫外线照射产生了一个交联DNA的双硝基咪唑中间体。在紫外照射下释放胺效应氮芥，4号植株的ICL产量较高。
Four novel photoactivated binitroimidazole prodrugs were synthesized. These agents produced DNA interstrand cross-links (ICLs) and direct strand breaks (DSB) upon UV irradiation, whereas no or very few DNA ICLs and DSBs were observed without UV treatment. Although these four molecules (1-4) contain the same binitroimidazole moiety, they bear four different leaving groups, which resulted in their producing different yields of DNA damage. Compound 4, with nitrogen mustard as a leaving group, showed the highest ICL yield. Surprisingly, compounds 1-3, without any alkylating functional group, also induced DNA ICL formation, although they did so with lower yields, which suggested that the binitroimidazole moiety released from UV irradiation Of 1-3 is capable of cross-linking DNA. The DNA cross-linked products induced by these compounds were completely destroyed upon 1.0 M piperidine treatment at 90 degrees C (leading to cleavage at dG sites), which revealed that DNA cross-linking mainly occurred via alkylation of dGs. We proposed a possible mechanism by which alkylating agents were released from these compounds. HRMS and NMR analysis confirmed that free nitrogen mustards were generated by UV irradiation of 4. Suppression of DNA ICL and DSB formation by a radical trap, TEMPO, indicated the involvement of free radicals it, the photo reactions of 3 and 4 with DNA. On the basis of these data, We propose that UV irradiation of compounds 1-4 generated a binitroimidazole intermediate that cross-links DNA. The higher ICL yield observed with 4 resulted from the amine effector nitrogen mustard released from UV irradiation.