EXOCYCLIC DNA ADDUCTS--SYNTHETIC AND ANALYTIC STUDIES

外环 DNA 加合物——合成和分析研究

• 批准号: 6416841
• 负责人: FRANCIS JOHNSON
• 金额: $ 11.52万
• 依托单位: STATE UNIVERSITY NEW YORK STONY BROOK
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-02-01 至 2002-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6416841
• 关键词: DNA damage; DNA repair; acrolein; adduct; analytical chemistry; carmustine; crosslink; deoxyadenosines; enzyme mechanism; glycosylation; lipid peroxides; nucleic acid chemical synthesis; nucleoside analog; nucleosides; oligonucleotides; protective chemical group; synthetic nucleic acid; synthetic nucleotide; vinyledene chloride

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.

描述：（申请人的描述）该程序本节中描述的有机，合成和分析化学旨在支持随附项目中的生物学和物理化学研究。主要目标是为合成DNA低聚物的DMT-磷酰胺（在必要时在N保护）的形式提供改良的2'-脱氧核苷。 修饰的核苷包含三组：（a）那些代表或模仿由电泳或反应性氧化物种诱导的或模仿损伤的核苷的核苷，（b）那些是非溶质化的自然底物的DNA修复酶研究的正常自然底物的模仿，而激活后的核底物则将形成欧外循环添加的交叉或互际固定。两个主要主题主导合成化学。 第一个涉及在核苷侧链中具有替代性甘氨酸，可以将其通过周期氧化转化为醛。 后者将在单周期内生成所需的加合物。 通过这种方法，将与甲醛，甲醛，脂质过氧化加合物，天然无碱性位点和核糖酮有关的加合物通过这种方法进行原位合成。 这种方法也将生成交联。 第二个主题涉及将“ Carba”嘌呤和嘧啶用作正常碱基的稳定或不可用的模拟物，以及内源性DNA损伤的氧化或加入形式。 这些将被使用：（a）在涉及的研究中，通过这种机制，DNA修复酶（例如muty）操作，包括纵向（flip-out）过程，（b）用于研究诱变机制的研究，以及（c）获得具有DNA修复酶的复合物的晶体结构。