Comparative analysis of DNA alkylation by conjugates between pyrrole-imidazole hairpin polyamides and chlorambucil or seco-CBI
Comparative analysis of DNA alkylation by conjugates between pyrrole-imidazole hairpin polyamides and chlorambucil or seco-CBI
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DOI：
10.1016/j.bmc.2009.12.033
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发表时间：
2010-02-01
影响因子：
3.5
通讯作者：
Sugiyama, Hiroshi
中科院分区：
文献类型：
--
作者：
Minoshima, Masafumi;Bando, Toshikazu;Sugiyama, Hiroshi
我们使用N-甲基吡咯（Py）-N-甲基咪唑（Im）聚酰胺和DNA烷基化剂苯丁酸氮芥或1-（氯甲基）-5-羟基-1，2-二氢-3H-苯并[e]吲哚（seco-CBI）之间的缀合物研究了序列特异性DNA烷基化。聚酰胺-苯丁酸氮芥缀合物1-4的不同之处在于DNA烷基化苯丁酸氮芥部分与Py-Im聚酰胺结合的位置。高分辨率变性聚丙烯酰胺凝胶电泳（PAGE）显示，苯丁酸氮芥共轭1-4烷基化的DNA的序列识别的Py-Im聚酰胺核心部分。反应性和序列特异性受缀合位置的影响很大，这反映了DNA小沟中烷化剂的几何形状。合成聚酰胺-断-CBI缀合物5以比较苯丁酸氮芥与断-CBI作为Py-Im聚酰胺的烷基化部分的功效。变性PAGE分析显示，聚酰胺-断-CBI缀合物5的DNA烷基化活性与聚酰胺-苯丁酸氮芥缀合物1和2的DNA烷基化活性相似。相反，缀合物5的细胞毒性上级缀合物1-4的细胞毒性。这些结果表明，与苯丁酸氮芥缀合物相比，开环-CBI缀合物在细胞中具有明显的活性。这些结果可能有助于开发更特异和更有活性的DNA烷化剂。(C)2009爱思唯尔有限公司保留所有权利。
We investigated sequence-specific DNA alkylation using conjugates between the N-methylpyrrole(Py)-N-methylimidazole (Im) polyamide and the DNA alkylating agent, chlorambucil, or 1-(chloromethyl)-5-hydroxy-1,2-dihydro-3H-benz[e] indole (seco-CBI). Polyamide-chlorambucil conjugates 1-4 differed in the position at which the DNA alkylating chlorambucil moiety was bound to the Py-Im polyamide. High-resolution denaturing polyacrylamide gel electrophoresis (PAGE) revealed that chlorambucil conjugates 1-4 alkylated DNA at the sequences recognized by the Py-Im polyamide core moiety. Reactivity and sequence specificity were greatly affected by the conjugation position, which reflects the geometry of the alkylating agent in the DNA minor groove. Polyamide-seco-CBI conjugate 5 was synthesized to compare the efficacy of chlorambucil with that of seco-CBI as an alkylating moiety for Py-Im polyamides. Denaturing PAGE analysis revealed that DNA alkylation activity of polyamide-seco-CBI conjugate 5 was similar to that of polyamide-chlorambucil conjugates 1 and 2. In contrast, the cytotoxicity of conjugate 5 was superior to that of conjugates 1-4. These results suggest that the seco-CBI conjugate was distinctly active in cells compared to the chlorambucil conjugates. These results may contribute to the development of more specific and active DNA alkylating agents. (C) 2009 Elsevier Ltd. All rights reserved.