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

基本信息

批准号：
8119100
负责人：
Carmelo J Rizzo
金额：
$ 28.25万
依托单位：
VANDERBILT UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-08-01 至 2011-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8119100
关键词：
2-butenal 3,4-epoxy-1-butene 4 hydroxynonenal Acrolein Address Aging Aldehydes Alkylating Agents Alkylation Binding Biological Biology Bypass COS-7 Cell Carbon Carcinogens Cells Chemistry Complex DNA DNA Adducts DNA Intrastrand Crosslinking DNA biosynthesis Deamination Deoxyadenosines Deoxycytidine Development ERCC1 gene Environmental Pollutants Epoxy Compounds Evaluation Exposure to Fanconi&apos s Anemia Frameshift Mutation Free Radicals Funding Glyoxal Grant Health Human Hydrolysis In Vitro Individual Investigation Knockout Mice Label Laboratories Lead Lesion Link Lipid Peroxidation Malignant Neoplasms Mammalian Cell Mediating Microsatellite Instability Minor Groove Mismatch Repair Molecular Molecular Biology Molecular Conformation Mus Mutagens Nucleosides Nucleotides Oligonucleotides Organic Synthesis Oxidative Stress Parents Phenotype Play Polymerase Premature aging syndrome Process Radioisotope Dilution Technique Reaction Research Design Role Route Sampling Scheme Site Site-Directed Mutagenesis Source Structure Tissue Sample Ursidae Family Vinyl Chloride Work adduct calf thymus DNA carcinogenicity chloroethylene oxide crosslink dimethyl sulfate direct application ds-DNA in vivo interest monomer programs repaired stable isotope stereochemistry structural biology

项目摘要

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.

该计划项目交互地使用有机合成、生物分析化学、结构生物学和分子生物学阐明外源性和内源性双功能分子的分子细节烷基化加合物会降解 DNA 复制和修复。工作重点将集中在两个站点的代理商上 DNA 可能发生的亲核攻击被两个或三个碳原子隔开。氯环氧乙烷氯乙烯的代谢物是前者的一个例子，α，β-不饱和醛，例如丙烯醛，巴豆醛和4-羟基壬烯醛是后者的例子。本计划的中心假设项目是双亲电子试剂可以形成链间和链内 DNA 交联，这种交联有助于加合物的生物学意义重大。项目 1 将开发由这些物质形成的各种类型加合物的合成路线亲电子试剂及其通过确定的区域化学位点特异性掺入 DNA 的策略立体化学。拟议的研究旨在解决有关以下方面的假设：1）链内交联的表征以及损伤对链内交联的处理绕过聚合酶； 2)氯环氧乙烷与丙烯醛N1-dA和N3-dC加合物的合成与研究及其脱氨基产物； 3) 鉴定生物样品中烯醇的 DNA 交联；4) 来自 N7-dG 加合物水解的 FAPgamma 损伤的合成和表征。待研究的 DNA 加合物源自广泛分散的环境污染物或产生内源性通过脂质过氧化作用。鉴于人们广泛接触这些化合物，我们的研究将对人类健康问题有直接的应用。