Pyrimidine ring opening in the unimolecular dediazoniation of guanine diazonium ion. An ab initio theoretical study of the mechanism of nitrosative guanosine deamination
Pyrimidine ring opening in the unimolecular dediazoniation of guanine diazonium ion. An ab initio theoretical study of the mechanism of nitrosative guanosine deamination
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DOI：
10.1021/ja961334k
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发表时间：
1996-11-06
影响因子：
15
通讯作者：
Son, MS
中科院分区：
文献类型：
--
作者：
Glaser, R;Son, MS
DNA碱基脱氨和与HNO2或NO反应引起的链间交联与人类的各种疾病有关。1一氧化氮在体外可使核苷、核苷酸和DNA脱氨基，体内也可发生类似的DNA损伤。2腺嘌呤的氨基可以通过重氮化反应消除，3胞嘧啶脱氨基为尿嘧啶是众所周知的诱变事件。4，5鸟嘌呤与HNO2脱氨反应生成黄嘌呤(方案1)或使6，7与邻近的鸟嘌呤或腺嘌呤发生交联反应。8 DNA碱基的脱氨反应被认为涉及重氮离子作为关键的反应中间体，机理假说是基于产物分析及其合理性，类似于芳香伯胺的化学。9然而，与苯胺不同的是，DNA碱基的重氮离子从未被直接观察到，它们的性质、稳定性和反应性尚不清楚。方案1概述了水与鸟嘌呤重氮离子GN2+(1)反应的机理假设。前面讨论的三种主要机理都导致了N_2+被羟基取代，然后互变异构为黄嘌呤，它们在N_2消除和羟基加成(+H_2O/-H+)的时间上有所不同。如果H2O攻击重氮官能团所连接的C原子，则发生亲核芳香族取代反应，并以单分子(SNAr1)或双分子(SN-Ar2)的方式生成黄嘌呤。硝基鸟嘌呤是一种已知的副产物，它的形成表明是SN1类型的过程。或者，亲核剂可以加到N-β上，而双氮烯可以排出氮气。在交联型构型中，认为另一个DNA碱基的氨基起亲核作用，Shapiro机理与Verly动力学数据一致。10用寡脱氧核苷酸双链体11a进行了研究，观察到的序列偏好通过涉及重氮离子11a的邻近效应得到了合理的解释，并得到了理论研究的证实。11B在此背景下，Makino et al.12人发现，在2‘-脱氧鸟苷、寡脱氧核苷酸和小牛胸腺的亚硝化反应中形成了超过20%的2’-脱氧鸟苷。目前还没有被接受的鸟嘌呤脱胺机制来解释草苷产品，也没有提出任何假设。在这里，我们报告了1的单分子去重氮化的从头计算研究结果(图1)，解释了Makino等人的实验发现。12，为今后的实验研究提供了一个力学假说。在RHF/6-31G*水平上进行了结构优化和振动分析，电子关联效应在冻结核近似和RHF/6-31G*结构下用三阶微扰理论进行了近似(表1)。对Rn2+(R)H，13bMe，13a，Cet，13aPh13d的理论模型相关性的系统研究表明，在这个理论水平上，实验和理论符合得很好[MP3(FC)/6-31G*//RHF/6-31G*+0.9ΔVZPE-
DNA base deamination and interstrand cross-linking due to reaction with HNO2 or NO has been linked to a variety of disorders in people. 1 Nitric oxide deaminates nucleosides, nucleotides, and DNA in vitro, and similar DNA damage also occurs in vivo. 2 The amino group of adenine can be eliminated via diazotization reactions, 3 and deamination of cytosine to uracil is a well-known mutagenic event. 4, 5 The deamination of guanine with HNO2 leads to xanthine formation (Scheme 1) or crosslinking6, 7 to a proximate guanine or adenine. 8 The deaminations of the DNA bases are thought to involve diazonium ions as the crucial reactive intermediate, and the mechanistic hypotheses are based on product analyses and their rationalization in analogy to the chemistry of aromatic primary amines. 9 In contrast to aniline, however, the diazonium ions of the DNA bases have never been observed directly, and their properties, stabilities, and reactivities are not known. The mechanistic hypotheses for the reaction of water with the guanine diazonium ion GN2+(1) are outlined in Scheme 1. The three principle mechanisms previously discussed all result in the replacement of the N2+ function by the OH group, followed by tautomerization to xanthine, and they differ in the timing of N2 elimination and hydroxyl group addition (+ H2O/-H+). If H2O attacks the C-atom to which the diazonio function is attached, nucleophilic aromatic substitution occurs with N2 loss and formation of xanthine in a uni-(SNAr1) or bimolecular (SN-Ar2) fashion. Nitroguanine is a known side product, and its formation is indicative of an SN1 type process. Alternatively, a nucleophile may add to Nβ and the diazene may undergo N2 expulsion. In cross-link formations, it is thought that the amino group of another DNA base serves as the nucleophile, and the Shapiro mechanism is consistent with the Verly kinetic data. 10 The cross-linking was studied with oligodeoxynucleotide duplexes, 11a and the observed sequence preferences were rationalized by proximity effects involving the diazonium ion11a and corroborated by theoretical study. 11b On this background, Makino et al. 12 have discovered that in excess of 20% of 2′-deoxyoxanosine was formed in the nitrosations of 2′-deoxyguanosine, oligodeoxynucleotide, and calf thymus. No currently accepted mechanism for guanine deamination accounts for the oxanosine product, and no postulates have been advanced. Here, we report the results of an ab initio study of the unimolecular dediazoniation of 1 (Figure 1) that explains the experimental findings by Makino et al. 12 and provides a mechanistic hypothesis for future experimental investigations. Structure optimizations and vibrational analyses were carried out at the RHF/6-31G* level, and electron correlation effects were approximated with third-order Møller-Plesset perturbation theory in the frozen core approximation and with the RHF/6-31G* structures (Table 1). Systematic studies of theoretical model dependencies of RN2+(R) H, 13b Me, 13a, c Et, 13a Ph13d) show excellent agreement between experiment and theory at this theoretical level [MP3 (fc)/6-31G*//RHF/6-31G*+ 0.9 ΔVZPE-