EXOCYCLIC DNA ADDUCTS--SYNTHETIC AND ANALYTIC STUDIES

产品说明：（申请人的描述）有机，合成和分析化学在该计划的这一部分中描述的目的是支持生物和物理化学研究在伴随的项目。主要目标是提供以其DMT-亚磷酰胺（必要时N-保护的）形式衍生的修饰的2 ′-脱氧核苷用于合成DNA寡聚物。 修饰的核苷包括三组：（a）代表或模拟由亲电体或由反应性氧化物质在DNA中诱导的损伤的那些，（B）作为用于DNA修复酶研究的正常天然底物的不可水解模拟物的那些，和活化后将形成环外加合物或链间交联的那些。两个主要的主题支配着合成化学。 第一种涉及在核苷侧链中具有邻位二醇，其可以通过高碘酸盐氧化转化为醛。 后者将在合成后产生所需的加合碱基。 与芳醛、巴豆醛、脂质过氧化加合物、天然脱碱基位点和核糖内酯相关的加合物将通过该方法原位合成。 这种方法也会产生交叉链接。 第二个主题涉及使用“卡巴”嘌呤和嘧啶作为正常碱基和氧化或加合形式的内源性DNA损伤的稳定或不可水解的模拟物。 这些将用于：（a）在涉及DNA修复酶（如MutY）操作机制的研究中，包括外翻（翻转）过程，（B）用于诱变机制的研究，以及（c）获得与DNA修复酶的复合物的晶体结构。

DESCRIPTION: (Applicant's Description) The organic, synthetic, and analytical chemistry described in this section of the program is designed to support biological and physico-chemical studies in the accompanying projects. The primary goal is to provide modified 2'-deoxynucleosides derivatized in the form of their DMT-phosphoramidites (N-protected where necessary) for synthetic DNA oligomers. The modified nucleosides comprise three groups: (a) those that represent or mimic damage induced in DNA by electrophiles or by reactive oxidizing species, (b) those that are non-hydrolysable mimics of the normal natural substrates for studies of DNA repair enzymes, and those that after activation will form exocyclic adducts or inter-strand crosslinks. Two main themes dominate the synthetic chemistry. The first involves having a vicinal glycol in a nucleoside side-chain that by periodate oxidation can be converted to an aldehyde. The latter will generate the desired adducted base, post-synthetically. Adducts related to araldehyde, crotonaldehyde, lipid peroxidation adducts, the natural abasic site, and ribonolactone will be synthesized in situ by this method. Cross-links also will be generated by this approach. The second theme concerns the use of "carba" purines and pyrimidines as stable or non-hydrolysable mimics of both normal bases and oxidized or adducted forms of endogenous DNA damage. These will be used: (a) in studies involving mechanisms by which DNA repair enzymes such as MutY operate, including the eversion (flip-out) process, (b) for studies of mutagenic mechanisms, and (c) to obtain crystal structures of complexes with DNA repair enzymes.