Department of Chemistry and Biochemistry, University of Maryland, Baltimore County, 1000 Hilltop Circle, Baltimore, MD 21228, USA.
Chem Res Toxicol. 2010 Jul 19;23(7):1223-33. doi: 10.1021/tx100093a.
A number of putative purine nucleoside and nucleobase adducts of the diazonium ion derived from 3-hydroxy-N-nitrosomorpholine have been synthesized as dimethylacetals. These are converted, in most cases nearly quantitatively, to the aldehydes, or in two cases to their derivatives, on treatment with mild acid to yield standards for a quantitative investigation of alkylation of purine nucleosides and DNA by the above metabolite of the powerful carcinogen N-nitrosomorpholine. The stability of the resulting nucleobase ethoxyacetaldehyde (EA) adducts has been characterized under a number of conditions with respect to their propensity to decompose. The stabilities, compared to that of the previously characterized adduct of the model benzimidazole, are generally unexceptional. Deposition of adducts on purine nucleosides and DNA were quantified in reactions in which 3-hydroperoxy-N-nitrosomorpholine was reduced to the hydroxy metabolite by a water-soluble phosphine at 21 +/- 2 degrees C. The adduct profile is highly similar to that observed from simpler alpha-hydroxy metabolites of acyclic dialkylnitrosamines, with the three most abundant ethoxyacetaldehyde (EA) adducts in reactions of duplex DNA being N7-EA-Gua approximately O(6)-EA-Gua > N3-EA-Ade. The initial rate kinetics of formation of hydroxyethyl (HE) lesions from the initially formed EA lesions have been determined in the case of the major products in the cases of both the nucleoside and DNA adducts. The rates of formation of HE adducts are accelerated in DNA, relative to the nucleosides in the cases of the N7-EA-Ade, N7-EA-Gua, and O(6)-EA-Gua adducts by factors of 7, 14, and 54, respectively. The initial rates of depurination of the N3-EA-Ade, N7-EA-Gua, and N7-EA-Gua adducts have also been quantified, and they are unexceptional in comparison with what has been previously reported for simple alkyl adducts. The adduct profiles reported here stand in significant contrast to what has been reported previously for structurally closely related alpha-substituted cyclic nitrosamines. In part or whole, this may be due to methodological differences in the conduct of the present and previous reports.
已经合成了 3-羟基-N-亚硝脒衍生的重氮离子的一些假定嘌呤核苷和碱基加合物作为二甲缩醛。在温和酸处理下，这些加合物在大多数情况下几乎定量转化为醛，在两种情况下转化为它们的衍生物，以产生定量研究上述致癌剂 N-亚硝脒啉代谢物对嘌呤核苷和 DNA 烷基化的标准。已经研究了在多种条件下得到的碱基乙氧基乙醛（EA）加合物的稳定性，以了解它们分解的倾向。与以前表征的模型苯并咪唑加合物相比，稳定性通常没有异常。在 21±2°C 下，水溶性膦将 3-过氧基-N-亚硝脒还原为羟基代谢物的反应中，定量测定了 3-羟基-N-亚硝脒啉在嘌呤核苷和 DNA 上的加合物沉积。加合物谱与无环二烷基亚硝胺的简单α-羟基代谢物观察到的非常相似，在双链 DNA 的反应中，三种最丰富的乙氧基乙醛（EA）加合物为 N7-EA-Gua≈O(6)-EA-Gua>N3-EA-Ade。在核苷和 DNA 加合物的主要产物的情况下，已经确定了从最初形成的 EA 损伤形成羟乙基（HE）损伤的初始形成动力学。在 N7-EA-Ade、N7-EA-Gua 和 O(6)-EA-Gua 加合物的情况下，与核苷相比，DNA 中 HE 加合物的形成速度分别加快了 7、14 和 54 倍。还定量测定了 N3-EA-Ade、N7-EA-Gua 和 N7-EA-Gua 加合物的去嘌呤化初始速率，与以前报道的简单烷基加合物相比，它们没有异常。与以前报道的结构上密切相关的α取代环亚硝胺相比，这里报道的加合物谱形成了显著的对比。部分或全部原因可能是本报告和以前报告中进行方法上的差异。
