Nucleoside and DNA adducts from N-nitrosotolazoline.
Nucleoside and DNA adducts from N-nitrosotolazoline.
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N-亚硝基唑啉的核苷和 DNA 加合物。
DOI：
10.1021/tx700323k
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发表时间：
2008
影响因子：
4.1
通讯作者：
Shi,Jianzheng
中科院分区：
文献类型：
--
作者：
Loeppky,RichardN;Shi,Jianzheng
N-亚硝基妥拉唑啉（代表性咪唑啉受体药物妥拉唑啉的亚硝化产物）与DNA、脱氧鸟苷（dG）或脱氧腺苷（dA）的反应产生含有2-苯乙酰胺基乙基的加合物。本文报道了2-苯乙酰胺基乙基鸟嘌呤衍生物（O 6-dG、O 6-Gua、N2-Gua和7-Gua）和2-苯乙酰胺基乙基腺嘌呤衍生物（1-Ade、3-Ade、7-Ade和N6-Ade）的合成和表征。除了利用已建立的紫外光谱法确定烷基腺嘌呤的结构外，还提出了一种新的测定N-烷基化位点的~（13）C NMR方法。N-亚硝基妥拉唑啉与dG反应生成7-（2-苯乙酰胺乙基）脱氧鸟苷（主要产物）、O-6-（2-苯乙酰胺乙基）脱氧鸟苷和5′-O-苯乙酰脱氧鸟苷。N-亚硝基妥拉唑啉与dA反应生成1-、3-、7-、N6和5-O′-2-苯乙酰胺基乙基腺嘌呤和dA衍生物以及几种苯乙酰加合物。N-亚硝基妥拉唑啉在体外与DNA反应，可检测到2-苯乙酰胺基乙基加合物（加合物，相对%）：7-Gua，60%; 3-Ade，30%; O-6-Gua，8%;和7-Ade，2%。比较这些数据与适当的文献数据，以及我们的工作的机制ofN-亚硝基妥拉唑啉水解，是一致的加合物产生的2-苯乙酰胺乙基重氮中间体。结果表明，N-亚硝基妥拉唑啉，并推测其他N-亚硝基咪唑啉，如果产生的内源性亚硝化途径，能够烷基化DNA没有额外的代谢转化，是可能的致癌物。
The reaction ofN-nitrosotolazoline, the nitrosation product of a representative imidazoline receptor drug tolazoline, with DNA, deoxyguanosine (dG), or deoxyadenosine (dA) produces adducts containing the 2-phenylacetamidoethyl group. The synthesis and characterization of 2-phenylacetamidoethyl-guanine derivatives (O6-dG, O6-Gua, N2-Gua, and 7-Gua) and 2-phenylacetamidoethyladenine derivatives (1-Ade, 3-Ade, 7-Ade, and N6-Ade) are described. In addition to the use of an established UV spectral method for confirming the structure of the alkyl adenines, a new13C NMR method for determining theN-alkylation site is presented. In combination with the synthesized standards, HPLC MS/MS methods were used to determine the nature and the quantity of adducts produced.N-Nitrosotolazoline reacted with dG to give 7-(2-phenylacetamidoethyl)deoxyguanosine (major), O6-(2-phenylacetamidoethyl)deoxyguanosine, and 5′-O-phenyacetyldeoxyguanosine. The reaction ofN-nitrosotolazoline with dA produced the 1-, 3-, 7-, N6, and 5-O′-2-phenylacetamidoethyl adenine and dA derivatives as well as several phenylacetyl adducts. Reaction ofN-nitrosotolazoline with DNA in vitro resulted in the detection of 2-phenylacetamidoethyl adducts (adduct, relative %): 7-Gua, 60%; 3-Ade, 30%; O6-Gua, 8%; and 7-Ade, 2%. Comparison of these data with appropriate literature data, as well as our work on the mechanism ofN-nitrosotolazoline hydrolytic decomposition, is consistent with the adducts being produced from a 2-phenylacetamidoethyldiazonium intermediate. The results show thatN-nitrosotolazoline, and presumably otherN-nitrosoimidazolines, if produced by endogenous nitrosation pathways, are capable of alkylating DNA without additional metabolic transformation and are probable carcinogens.