Activation barriers for DNA alkylation by carcinogenic methane diazonium ions
Activation barriers for DNA alkylation by carcinogenic methane diazonium ions
复制标题
DOI：
10.1002/jcc.20334
复制
发表时间：
2006-02-01
影响因子：
3
通讯作者：
LeBreton, PR
中科院分区：
文献类型：
--
作者：
Ekanayake, KS;LeBreton, PR
考察了DNA碱基与甲烷重氮离子的甲基化反应，甲烷重氮离子是几种致癌甲基化试剂形成的反应中间体。用B3LYP密度泛函方法计算了鸟嘌呤N7、N3和O-6，腺嘌呤N7、N3和N1，胞嘧啶N3和O-6，胸腺嘧啶ANDO(2)和O-4甲基化反应的S，2个过渡态。用类导体极化连续体方法和离散/SCRF相结合的方法研究了溶剂化效应。鸟嘌呤N3、腺嘌呤N7和腺嘌呤NI上反应的过渡态受甲烷重氮离子和外环氨基之间的空间相互作用的影响。在气相和水溶液中，N原子上的甲基化反应具有更松散的过渡态，并且通常比O原子上的反应更早发生在反应路径上。水中过渡态的成键比气相的短0.03~0.13A，活化能高出13~35kcal/mol。用三个水分子的碱水络合物进行离散/SCRF联合溶剂化能计算，得到的碱溶剂化能比用CPCM连续体方法得到的结果要大，尤其是胞嘧啶。用离散/SCRF方法得到的势垒计算的反应性与实验观察到的鸟嘌呤在N7的高反应性是一致的。(C)2005年威利期刊公司。
Methylation reactions of the DNA bases with the methane diazonium ion, which is the reactive intermediate formed from several carcinogenic methylating agents, were examined. The S,2 transition states of the methylation reactions at N7, N3, and O-6 of guanine; N7, N3, and N1 of adenine; N3 and O-6 of cytosine; andO(2) and O-4 of thymine were calculated using the B3LYP density functional method. Solvation effects were examined using the conductor-like polarizable continuum method and the combined discrete/SCRF method. The transition states for reactions at guanine N3, adenine N7, and adenine NI are influenced by steric interactions between the methane diazonium ion and exocyclic amino groups. Both in the gas phase and in aqueous solution, the methylation reactions at N atoms have transition states that are looser, and generally occur earlier along the reaction pathways than reactions at O atoms. The forming bonds in the transition states in water are 0.03 to 0.13 A shorter than those observed in the gas phase, and the activation energies are 13 to 35 kcal/mol higher. The combined discrete/SCRF solvation energy calculations using base-water complexes with three water molecules yield base solvation energies that are larger than those obtained from the CPCM continuum method, especially for cytosine. Reactivities calculated using barriers obtained with the discrete/SCRF method are consistent with the experimentally observed high reactivity at N7 of guanine. (c) 2005 Wiley Periodicals, Inc.