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首页> 外文期刊>Chemical research in toxicology >Determinants of selectivity in alkylation of nucleosides and DNA by secondary diazonium ions: evidence for, and consequences of, a preassociation mechanism.
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Determinants of selectivity in alkylation of nucleosides and DNA by secondary diazonium ions: evidence for, and consequences of, a preassociation mechanism.

机译：二次重氮离子对核苷和DNA烷基化的选择性的决定因素：预缔合机理的证据和后果。

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摘要

Reactions have been carried out in which 1,3-diisopropyltriazene or N-isopropyl-N-(1-hydroxyethyl)nitrosamine has been decomposed in neutral, buffered aqueous media in the presence of ((15)N(2))2'-deoxyguanosine and ((15)N(6))2'-deoxyadenosine. The products of covalent attachment of the isopropyl cation, derived from the isopropyl diazonium ion, to the heteroatoms of the purines have been separated and quantified by HPLC/electrospray mass spectrometry by employing isotopically distinct synthetic standards. The results indicate that the two different precursors of the isopropyl cation result in the formation of different yields of products in the reactions at all of the heteroatoms of both purines, outside experimental error, except possibly in the case of the N3 position of dAdo. For the different alkylating agents, the ratios of yields at any two sites vary as well. This leads to the conclusion that isopropylation occurs by a preassociation mechanism in which the isopropyl cation intermediate reacts in the solvation shell in which it is generated from its precursors. The reaction of N-isopropyl-N-(1-hydroxyethyl)nitrosamine results in alkylation of 2'-deoxyguanosine in preference to 2-deoxyadenosine, by a factor of 3-4. In this reaction, the yields for reaction at N1, N3, N(6), and N7 of adenine vary over less than a factor of 2, whereas the yields for N(2), N3, O(6), and N7 of guanine vary over less than a factor of 4. The N1 atom of guanine is disfavored over the major product, the O(6) adduct, by a factor of <8. The reaction of 1,3-diisopropyltriazene shows a similar preference for alkylation of 2-deoxyguanosine, with a similar range of product distribution in the reactions at adenine heteroatoms and a somewhat larger range of distribution at guanine heteroatoms. In particular, the yield of 1-isopropylguanosine is 50-fold lower than that of O(6)-isopropylguanosine. The comparable yields of products of reaction at the "hard" and "soft" sites of the purines lead to the conclusion that nucleophilicity isunimportant in site selectivity of alkylation by the isopropyl cation. The noteworthy selectivities, above, are rationalized by: differences in the association constants of the precursors of the cations with the two nucleosides; steric, statistical, and electrostatic effects that favor reaction of the O(6) atom of guanine; and larger steric and/or desolvation requirements for association of the 1,3-diisopropyltriazenium cation with the N1 atom of guanine. The reaction of N-isopropyl-N-(1-hydroxyethyl)nitrosamine with double-stranded DNA has been similarly analyzed. The product distribution is remarkably similar in profile to that observed for the nucleosides in solution. In particular, exocyclic amino groups are competitive with the more traditional sites of diazonium ion-mediated alkylation. A comparison to earlier literature data on alkylation by methyl- and ethyl-diazonium ions illustrates some fundamental differences between the reaction of the diazonium ions and the isopropyl cation derived from the isopropyl diazonium ion.
机译：已经进行了反应，其中在（（15）N（2））2'-的存在下，在中性的缓冲水性介质中将1，3-二异丙基三氮烯或N-异丙基-N-（1-羟乙基）亚硝胺分解。脱氧鸟苷和（（15）N（6））2'-脱氧腺苷。异丙基重氮盐衍生的异丙基阳离子与嘌呤杂原子的共价结合产物已通过HPLC /电喷雾质谱法分离和定量，采用同位素不同的合成标准品进行了定量。结果表明，异丙基阳离子的两种不同前体导致在两个嘌呤的所有杂原子的反应中形成不同收率的产物，但实验误差除外，可能在dAdo的N3位置除外。对于不同的烷基化剂，任意两个位点的收率比例也不同。这得出结论，异丙基化是通过预缔合机理发生的，在该机理中，异丙基阳离子中间体在其前体中生成的溶剂化壳中发生反应。 N-异丙基-N-（1-羟乙基）亚硝胺的反应导致2'-脱氧鸟苷的烷基化优先于2-脱氧腺苷的烷基化3-4倍。在此反应中，腺嘌呤在N1，N3，N（6）和N7的反应收率变化小于2倍，而N（2），N3，O（6）和N7的收率变化不超过2。鸟嘌呤的变化小于四分之一。鸟嘌呤的N1原子优于主要产物O（6）加合物，其变化小于八分之一。 1，3-二异丙基三氮烯的反应显示出对2-脱氧鸟苷烷基化的相似偏好，在腺嘌呤杂原子上的反应中产物分布范围相似，而在鸟嘌呤杂原子上的分布范围更大。特别是，1-异丙基鸟苷的产率比O（6）-异丙基鸟苷的产率低50倍。在嘌呤的“硬”和“软”位点反应产物的可比产率得出的结论是，亲核性在异丙基阳离子对烷基化的位点选择性中并不重要。上面值得注意的选择性可以通过以下方式合理化：阳离子前体与两个核苷的缔合常数的差异;有利于鸟嘌呤O（6）原子反应的空间，统计和静电效应; 1,3-二异丙基三氮杂阳离子与鸟嘌呤的N1原子缔合的空间和/或去溶剂化要求更高。类似地分析了N-异丙基-N-（1-羟乙基）亚硝胺与双链DNA的反应。产物分布在轮廓上与溶液中核苷所观察到的相似。特别地，环外氨基与重氮离子介导的烷基化的更传统的位点竞争。与先前关于甲基和乙基重氮离子烷基化的文献数据的比较表明，重氮离子与衍生自异丙基重氮离子的异丙基阳离子的反应之间存在一些基本差异。

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