Deamination and Dimroth rearrangement of deoxyadenosine-styrene oxide adducts in DNA
Deamination and Dimroth rearrangement of deoxyadenosine-styrene oxide adducts in DNA
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DOI：
10.1021/tx980038d
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发表时间：
1998-07-01
影响因子：
4.1
通讯作者：
Dipple, A
中科院分区：
文献类型：
--
作者：
Barlow, T;Takeshita, J;Dipple, A
在氧化苯乙烯和脱氧腺苷1位环氮的反应中，环氧化物在-（苯基）碳和-碳上都被打开。形成的1-取代核苷是不稳定的，随后发生Dimroth重排生成n -6-取代脱氧腺苷或脱胺生成1-取代脱氧肌苷。n -6取代化合物也可由外环氮直接反应生成。动力学实验表明，1-取代脱氧腺苷-苯乙烯氧化物和1-取代腺苷-苯乙烯氧化物的相对脱胺速率相似。然而，β - 1取代的腺苷-苯乙烯氧化物的Dimroth重排速率比β - 1取代的脱氧腺苷-苯乙烯氧化物高2.3倍，α - 1取代的腺苷-苯乙烯氧化物的Dimroth重排速率比α - 1取代的脱氧腺苷-苯乙烯氧化物高1.5倍。氧化苯乙烯与[H-3]脱氧腺苷和[H-3]脱氧腺苷结合到天然DNA和变性DNA中反应生成的产物分析表明：脱氧核糖核酸双螺旋结构使脱氧核糖核酸形成的加合物水平比变性脱氧核糖核酸减少了5倍，但对天然脱氧核糖核酸中n -6取代脱氧腺苷或1-取代脱氧肌苷-苯乙烯氧化物加合物的形成没有完全的屏障。此外，在变性DNA和天然DNA中，相对于核苷的反应，产物分布发生了改变，有利于形成β - 1取代脱氧肌苷-苯乙烯氧化物加合物。在DNA反应中，n -6取代产物的保留构型与反转构型的比例高于核苷反应。这些实验表明除了n -6位外，脱氧腺苷1位的环氮在一定程度上可用于天然DNA的反应。在苯乙烯- dna反应中，1-取代腺嘌呤的形成可导致脱胺产物，其中两个沃森-克里克氢键位点都被破坏。
In reactions between styrene oxide and the ring nitrogen at the 1-position of deoxyadenosine, the epoxide is opened at both the alpha-(benzylic) and beta-carbons. The 1-substituted nucleosides formed are unstable and subsequently undergo either Dimroth rearrangement to give N-6-substituted deoxyadenosines or deamination to give 1-substituted deoxyinosines. alpha N-6-Substituted compounds are also formed from direct reaction at the exocyclic nitrogen. Kinetic experiments revealed that relative rates of deamination of 1-substituted deoxyadenosine-styrene oxides and 1-substituted adenosine-styrene oxides were similar. However, the rate of Dimroth rearrangement in beta 1-substituted adenosine-styrene oxides was similar to 2.3-fold greater than that of beta 1-substituted deoxyadenosine-styrene oxides and similar to 1.5-fold greater in alpha 1-substituted adenosine-styrene oxides relative to alpha 1-substituted deoxyadenosine-styrene oxides. Analysis of the products formed from reactions of styrene oxide with [H-3]deoxyadenosine and [H-3]deoxyadenosine incorporated into native and denatured DNA showed that; the double-helical DNA structure reduced the levels of adducts formed 5-fold relative to denatured DNA but did not present a complete barrier to formation of either N-6-substituted deoxyadenosine- or 1-substituted deoxyinosine-styrene oxide adducts in native DNA. Additionally, in denatured and native DNA the product distributions were altered in favor of formation of beta 1-substituted deoxyinosine-styrene oxide adducts with respect to reactions of the nucleoside. The ratio of retained to inverted configuration of alpha N-6-substituted products was higher in DNA than in nucleoside reactions. These experiments indicate that in addition to the N-6-position, the ring nitrogen at the 1-position of deoxyadenosine is available, to some extent, for reaction in native DNA. In styrene oxide-DNA reactions, formation of 1-substituted adenines can lead to deaminated products where both Watson-Crick hydrogen-bonding sites are disrupted.