Chemistry and DNA alkylation reactions of aziridinyl quinones: Development of an efficient alkylating agent of the phosphate backbone
Chemistry and DNA alkylation reactions of aziridinyl quinones: Development of an efficient alkylating agent of the phosphate backbone
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DOI：
10.1021/bi981204j
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发表时间：
1998-10-27
期刊：
影响因子：
2.9
通讯作者：
Xing, CG
中科院分区：
文献类型：
--
作者：
Skibo, EB;Xing, CG
这里描述了一系列氮丙基醌的详细的水解性研究，当质子化时，它们捕获亲核试剂。这项研究提供了亲核捕获的速率常数和质子化的氮丙基醌的pK(A)值的汇编。作为本研究的结果，得到了包括抗癌剂DZQ以及其他合成的苯醌衍生物在内的线性自由能关系。质子化的DZQ具有较高的pK(A)值3.8，这解释了在pH为4时，DZQ与其他相关的氮杂环喹酮加强了DNA的交联性。文献中常发现氮杂环上的氮杂环上发生了氮杂环丙基的质子化反应，但pK(A)值与取代基的关系表明存在离域作用，这一定是由O-质子化作用引起的。还考察了质子化的氮杂苯二酚的DNA烷基化反应。在这项研究开始时，我们假设这些“坚硬的”亲电体会使DNA的磷酸骨架烷基化。主体DNA被质子化的氮丙基醌烷基化的比例高达35%，这是通过将苯二酚生色团掺入DNA来判断的。DZQ烷基化六聚体的H-1-P-31核磁共振关联实验证实了磷酸盐烷基化的存在。我们的模拟研究呈现了DNA DZQ烷基化的新图景，其中N(7)和磷酸烷基化之间存在竞争。这部分研究的结论是，任何DNA烷基化试剂都应将磷酸盐骨架视为可能的靶标，并且最好通过H-1-P-31核磁共振相关实验来评估磷烷基化。最后，观察到苯并咪唑基的氮丙基醌2发生了氮杂环开环和氨乙基的水解脱除反应。该反应用于用氨基乙基标记DNA的磷酸骨架。这样的标签使阴离子磷酸盐成为阳离子，也可以用作生色团、自旋标记或其他部分与DNA的连接点。
Described herein are detailed hydrolytic studies of a series of aziridinyl quinones, which trap nucleophiles when protonated. This study provided a compilation of the rate constants for nucleophile trapping and of the pK(a) values for the protonated aziridinyl quinones. A linear free energy relationship, including the antitumor agent DZQ, as well as other synthetic quinone derivatives, was obtained as a result of this study. Protonated DZQ has the relatively high pK(a) value of 3.8, which explains the enhanced cross-linking of DNA by DZQ and other related aziridinyl quinones at pH 4. The literature often shows aziridinyl quinone protonation occurring at the aziridinyl nitrogen, but the dependence of pK(a) values on quinone substituents indicates the presence of delocalization, which must arise from O-protonation. Also investigated were the DNA alkylation reactions of protonated aziridinyl quinones. At the outset of this study, we postulated that these "hard" electrophiles would alkylate the phosphate backbone of DNA. Bulk DNA is up to 35% alkylated by protonated aziridinyl quinones as judged by the incorporation of the quinone chromophore into the DNA. The presence of phosphate alkylation was verified by a H-1-P-31 NMR correlation experiment with DZQ-alkylated hexamer. Our modeling studies present a new picture of DZQ alkylation of DNA, where there is competition between N(7) and phosphate alkylation. The conclusions of this part of our study are that the phosphate backbone should be considered as a possible target of any DNA-alkylating agent and that an assessment of phosphate alkylation is best made with a H-1-P-31 NMR correlation experiment. Finally, the benzimidazole-based aziridinyl quinone 2 was observed to undergo aziridine ring opening followed by hydrolytic removal of the aminoethyl group from the quinone ring. This reaction was used to tag the phosphate backbone of DNA with aminoethyl groups. Such tags render anionic phosphates cationic and could also be employed as points of attachment for chromophores, spin labels, or other moieties to DNA.