Project 1: Synthetic Approaches to Carcinogen-Linked Oxyoligonucleotides

项目 1：致癌物相关含氧寡核苷酸的合成方法

• 批准号: 7208780
• 负责人: Carmelo J Rizzo
• 金额: $ 28.86万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-08-01 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7208780
• 关键词: DNA damage; DNA directed DNA polymerase; adduct; alkylation; amination; biomarker; carcinogens; chemical carcinogen; chemical related neoplasm /cancer; crosslink; gene mutation; human tissue; mass spectrometry; method development; nucleic acid chemical synthesis; nucleic acid sequence; oligonucleotides; site directed mutagenesis

This Program Project interactively uses organic synthesis, bioanalytical chemistry, structural biology, and molecular biology to elucidate the molecular details by which exogenous and endogenous bifunctional alkylating adducts degrade DNA replication and repair. Efforts will focus on agents in which the two sites of possible nucleophilic attack by the DNA are separated by either two or three carbon atoms. Chlorooxirane, a metabolite of vinyl chloride, is an example of the former and alpha, beta-unsaturated aldehydes, such as acrolein, crotonaldehyde and 4-hydroxynonenal, are examples of the latter. A central hypothesis of this Program Project is that bis-electrophiles can form inter- and intrastrand DNA crosslinks and such crosslinks contribute significantly in the biology of the adducts. Project 1 will develop synthetic routes to the various types of adducts that can be formed by these electrophiles and strategies for their site-specific incorporation into DNA with defined regiochemistry and stereochemistry. The proposed studies are designed to address hypotheses concerning the following: 1) the characterization of intrastrand enal crosslinks and the processing of the intrastrand crosslinks by lesion bypass polymerases; 2) the synthesis and study of N1-dA and N3-dC adducts of Chlorooxirane and acrolein and their deamination products; 3) identification of DNA crosslinks of enals from biological samples and 4) the synthesis and characterization of FAPgamma lesions that are derived from hydrolysis of N7-dG adducts. The DNA adducts to be studied are derived from widely dispersed environmental pollutants or produced endogenously through lipid peroxidation. Given the wide exposure to these compounds, our studies will have direct applications to human health concerns.

该计划项目可以互动地使用有机合成，生物分析化学，结构生物学和 分子生物学，以阐明分子细节，外源和内源性双功能 烷基化合并降解DNA复制和修复。努力将集中于两个地点的代理商 DNA可能会通过两个或三个碳原子分离核激活。 Chlorooxirane，a 乙烯基氯化物的代谢产物是前者和α-β-不饱和醛的一个例子，例如丙烯醛， 克罗托醛醛和4-羟基烯烯是后者的例子。该计划的中心假设 项目是，双电噬蛋白可以形成间链和内部DNA交联，并且这种交联贡献 在加合物的生物学中显着。 项目1将开发到可以由这些类型的加合物形成的合成路线 电力和特定地点将其特定地点纳入DNA的策略，并具有定义 立体化学。拟议的研究旨在解决有关以下的假设：1） 术内映射交联的表征和通过病变的内链交联处理 旁路聚合酶； 2）Chlorooxirane和丙烯醛的N1-DA和N3-DC加合物的合成和研究 及其脱氨基产品； 3）鉴定来自生物样品的DNA交联和4） Fapgamma病变的合成和表征来自N7-DG加合物的水解。 要研究的DNA加合物来自广泛分散的环境污染物或产生 内源性通过脂质过氧化。考虑到这些化合物的广泛接触，我们的研究将 直接适用于人类健康问题。