CONFORMATIONAL STUDIES OF ADDUCTED OLIGODEOXYNUCLEOTIDES

描述(由申请人提供) 将对寡聚脱氧核苷酸进行结构研究-特异性 用氯乙烯代谢物的特定加合物修饰 环氧氯丙烷和氯乙醛，以及α，β-不饱和 醛包括丙烯醛、巴豆醛和羟基壬烯醛。内收部位 将是鸟嘌呤的N1、N2和N3位，以及 腺嘌呤和胞嘧啶的N3和N4位。我们的目标是关联 不同类别的环加成物之间的化学差异，以及 链内和链间具有结构和构象的交联物 DNA中的属性。反过来，在这个过程中得到的结构信息 该项目将与第二个项目的生物数据相关联。乙烯基 氯代谢物增加一个C2单位，而丙烯醛、巴豆醛和 在DNA碱基上添加一个C3单位。一类环加成物 被检查的被称为“远端”加合物。在这些物质中，羟基位于 羟乙基或羟丙基外环加合物位于 一种氨基氮。据推测，这些物质对DNA有很强的破坏性 结构，因为它们干扰沃森-克里克碱基配对。研究将会 要了解DNA双链是如何适应这些的 扭曲。另一类将被研究的环加合物被称为 “近端”加合物，其中环羟基乙基或 羟基丙基加合物与亚氨基氮相邻。为了这些 预期单齿加合物的开环形式是 附着在氨基上的氮将稳定在双链DNA中。努力将会 重点了解双链DNA如何调节这一位置 平衡，以及作为开环产物的醛是如何 由DNA双链提供。这一点很重要，因为乙醛曾经 形成的，具有使DNA交联的潜力。特定站点的结构 将检查在第二个项目中确定的DNA交联链，以及 DNA序列在控制交联中的作用。连接子长度的作用 (C2与C3)关于交联能力和由此产生的失真 还将检测由交联物引入双链DNA的情况。

DESCRIPTION (provided by applicant) Structural studies will be conducted on oligodeoxynucleotides site-specifically modified with specific adducts of the vinyl chloride metabolites chlorooxirane and chloroacetaldehyde, and the alpha, beta-unsaturated aldehydes acrolein, crotonaldehyde, and hydroxynonenal. The adduction sites will be the N1, N2, and N3 positions of guanine, the N1 and N6 positions of adenine, and the N3 and N4 positions of cytosine. The goal is to correlate differences in chemistry between different classes of cyclic adducts, and intra- and inter-strand crosslinks, with structural and conformational properties in DNA. In turn, the structural information derived in this project will be correlated with biological data from the second Project. Vinyl chloride metabolites add a C2 unit, whereas acrolein, crotonaldehyde, and hydroxynonerial add a C3 unit to the DNA base. One class of cyclic adducts to be examined are termed "distal" adducts. In these, a hydroxy group in the hydroxy ethano or hydroxy propano exocyclic adduct is positioned adjacent to an amino nitrogen. These are postulated to be highly disruptive to DNA structure because they interfere with Watson-Crick base pairing. Studies will be geared towards understanding how the DNA duplex accommodates these distortions. Another class of cyclic adducts to be examined are termed "proximal" adducts, in which a hydroxy group of the cyclic hydroxy ethano or hydroxy propano adduct is positioned adjacent to an imino nitrogen. For these it is anticipated that the ring-opened form in which the monodentate adduct is attached at the amino nitrogen will be stabilized in duplex DNA. Effort will focus on understanding how duplex DNA modulates the position of this equilibrium, and how the aldehyde that is the product of ring-opening is accommodated by the DNA duplex. This is important because the aldehyde, once formed, has the potential to crosslink the DNA. The structures of site-specific DNA crosslinks identified in the second Project will be examined, as will the role of DNA sequence in controlling crosslinking. The role of linker length (C2 versus C3) on the ability to crosslink and the resulting distortions introduced into duplex DNA by the crosslinks will also be examined.