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Atom site selectivity in DNA alkylation by primary diazonium ions.

机译：伯重氮离子在DNA烷基化反应中的原子位点选择性。

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摘要

Diazonium ions are reactive intermediates derived by metabolites of carcinogenic nitrosamines. They can react with DNA at many heteroatoms and form different adducts, which might eventually lead to cancer. Compared to other classical organic alkylating agents, simple diazonium ions react more selectively at oxygen atoms of nucleobases. The resulting oxygen adducts have been shown to be correlated with the mutagenicity of the parent nitrosamines. Therefore, it is of great importance to understand the factors that account for this preference of diazonium ions for oxygen atoms of nucleobases.;This work was carried out to study the site selectivity in DNA alkylation by primary diazonium ions using 1-propyldiazonium ion as a tool. The 1-propyldiazonium ion can generate both n-propylation and iso-propylation products. The yield of iso-propylation and the ratio of n-propylation to iso-propylation at a given heteroatom are roughly measurements of the association constant and nucleophilicity of the site to the diazonium ion, respectively. Therefore, the individual effect of the association constants and nulceophilicities on the product yields can be discussed.;Alkylation of DNA as well as its nucleoside monomers by 1-propyldiazonium ion was carried out. After hydrolysis, the percent yields of n-propylation and iso-propylation products were determined by HPLC and LC/MS. The variation in the iso-propylation yields in nucleoside reactions is small and relatively random. In DNA, however, preferential iso-propylation in the minor groove was observed, indicating that the double helix favors the association of 1-propyldiazonium in the minor groove. In the case of the ratio of n-propylation to iso-propylation, the variation is also small in nucleoside reactions. In DNA, however, the ratios of n-propylation to iso-propylation for some sites show significant enhancement, while the others show much smaller enhancement or remain almost the same as compared to the nucleosides. These results demonstrate that the double helix selectively enhances the nucleophilicities of certain sites. Thus, it is the structure of DNA that dictates the atom site selectivity in DNA alkylation by primary diazonium ions.
机译：重氮离子是致癌性亚硝胺代谢产物的反应性中间体。它们可以在许多杂原子上与DNA反应并形成不同的加合物，最终可能导致癌症。与其他经典的有机烷基化剂相比，简单的重氮离子在核碱基的氧原子上反应更具选择性。已显示所得的氧加合物与母体亚硝胺的致突变性相关。因此，了解导致重氮离子偏爱核碱基中氧原子的因素具有十分重要的意义;该工作旨在研究以1-丙基重氮离子为基础的伯重氮离子在DNA烷基化中的位点选择性。工具。 1-丙基重氮离子可同时生成正丙基化和异丙基化产物。在给定的杂原子上，异丙基化的收率和正丙基化与异丙基化之比分别大致是该位点与重氮离子的缔合常数和亲核性的量度。因此，可以讨论缔合常数和亲核性对产物收率的个体影响。进行了DNA及其核苷单体被1-丙基重氮离子烷基化。水解后，通过HPLC和LC / MS确定正丙基化和异丙基化产物的产率百分比。核苷反应中异丙基化收率的变化很小且相对随机。然而，在DNA中，观察到小沟中存在优先的异丙基化，这表明双螺旋有利于小沟中1-丙基重氮的缔合。在正丙基化与异丙基化的比率的情况下，核苷反应中的变化也很小。然而，在DNA中，某些位点的正丙基化与异丙基化之比显示出明显的增强，而其他位点显示出与核苷相比小得多的增强或保持几乎相同。这些结果表明，双螺旋选择性地增强了某些位点的亲核性。因此，DNA的结构决定了伯重氮离子在DNA烷基化反应中的原子位点选择性。

著录项

  • 作者

    Lu, Xuefang.;

  • 作者单位

    University of Maryland, Baltimore County.;

  • 授予单位 University of Maryland, Baltimore County.;
  • 学科 Chemistry Analytical.;Chemistry Organic.
  • 学位 Ph.D.
  • 年度 2009
  • 页码 293 p.
  • 总页数 293
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 化学;有机化学;
  • 关键词

  • 入库时间 2022-08-17 11:38:24

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