Fluorine as a Probe in Polycyclic Aromatic Hydrocarbon Carcinogenesis Studies
氟作为多环芳烃致癌研究中的探针
基本信息
- 批准号:7231596
- 负责人:
- 金额:$ 15.95万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2007
- 资助国家:美国
- 起止时间:2007-02-01 至 2011-01-31
- 项目状态:已结题
- 来源:
- 关键词:6-fluorobenzo(a)pyrene6-fluorobenzo(c)phenanthreneAccountingAdenineAdoptedAldehydesAlkylating AgentsAromatic HydrocarbonsAromatic Polycyclic HydrocarbonsBay RegionBeliefBindingBiologicalCarcinogensChargeChemistryChinese HamsterClassCodon NucleotidesCollaborationsComparative StudyCytochrome P450DNADNA AdductsDNA BindingDNA Binding AgentDNA DamageDNA Modification ProcessDNA ProbesDNA RepairDNA SequenceDNA StructureDNA biosynthesisDNA chemical synthesisDNA lesionDataDevelopmentEnvironmental PollutantsEpoxide 8Epoxy CompoundsEvaluationEventFluorineFoundationsFutureGenesGlycolGoalsGuanineHPRT1 geneHealthHumanHydrocarbonsHydroxyl RadicalHypoxanthine PhosphoribosyltransferaseInvestigationIsomerismLeadLiteratureMCF7 cellMetabolic ActivationMetabolismMethodologyMethodsMinorMolecular ConformationMolecular GeneticsMutagenesisNMR SpectroscopyNucleosidesObject AttachmentParentsPhasePhysical condensationPlayPolycyclic HydrocarbonsProcessPropertyProto-OncogenesPurinesRangeResearchRoleRouteSiteSolidSolutionsStilbenesStructureStructure-Activity RelationshipSulfonesSystemTherapeuticTimeadductanalogbasebenzo(c)phenanthrenecarcinogenesischemical synthesiscomparativeconformerenantiomerinsightinterestmethod developmentnovelnucleobasepurineresearch studyresponsetooltumortumorigenesistumorigenic
项目摘要
Many environmentally prevalent polycyclic aromatic hydrocarbons (PAHs) are metabolized in mammalian
systems to carcinogens that react with cellular DMA leading to adverse biological and health effects. This
occurs by metabolic activation of a PAH to 4 bay region diol epoxides that are DMA alkylants. These
metabolites form covalent adducts with the purine bases and it is the DMA damage induced by this process
that ultimately results in mutagenesis and tumorigenesis. Introduction of fluorine can substantially alter
biological activity of a PAH and its metabolites. For example, increased activity has been shown for 6-
fluorobenzo[c]phenanthrene (6-F-BcPh) compared to benzo[c]phenanthrene (BcPh), whereas 6-
fluorobenzo[a]pyrene (6-F-BaP) showed substantially decreased activity. In order to better understand the
structure-activity relationships on molecular-genetic level, studies using fluorinated PAHs and their
metabolites are proposed. For this, it is critical to have sufficient quantities of regiospecifically fluorinated
PAHs, and importantly, their fluorinated metabolites. Two lines of investigations are therefore proposed. (A)
Development of novel methods for synthesis of regiospecifically fluorinated PAHs, their putative metabolites
and physical as well as biological studies with these compounds. The fluorinated PAHs will be used in 2
types of collaborative studies. One involving mechanistic, theoretical and experimental charge distribution
studies and the other an evaluation of metabolic activation of the fluoro BcPh as well as dihydrodiols to DMA
alkylating agents and comparisons to the studied BcPh. BcPh-DNA adducts have been stated to be elusive
to DNA repair accounting for their higher activity. (B) Comparative physical and NMR studies of DNA
modified by inactive 6-F-BaP adducts with those modified by the highly active BaP diol epoxides. Data on
the latter is already available in the literature. For these studies DNA modified by 6-F-BaP diol epoxides will
be synthesized. Beginning from our prior synthesis of 6-F-BaP dihydrodiol, diastereoselective synthesis of
6-F-BaP diol epoxides will be developed (currently unprecedented). Using the synthetic diol epoxides,
nucleoside-diol epoxide adducts of 6-F-BaP will be synthesized and incorporated into biologically important
DNA sequences via modified solid-phase DNA synthesis. The structures of DNA site-specifically modified
by 6-F-BaP diol epoxides will be studied by NMR. This is to probe the influence of the F atom on DNA
conformation and for comparison of the structures to the protio analogs. These studies will provide insight
into subtle structural differences that lead to markedly different bioresponses.
许多环境中普遍存在的多环芳烃(PAHs)在哺乳动物体内代谢
系统的致癌物质与细胞的DMA反应,导致不良的生物和健康影响。这
通过PAH代谢活化为4种海湾地区二醇环氧化物(DMA烷化剂)而发生。这些
代谢产物与嘌呤碱基形成共价加合物,这是由该过程诱导的DMA损伤
最终导致突变和肿瘤发生。氟的引入可以显著改变
PAH及其代谢物的生物活性。例如,已显示6- 10天的活性增加。
与苯并[c]菲(BcPh)相比,6-氟苯并[c]菲(6-F-BcPh),而6-
氟苯并[a]芘(6-F-BaP)显示出显著降低的活性。为了更好地理解
分子遗传水平上的结构-活性关系,使用氟化多环芳烃及其
提出了代谢物。为此,关键的是具有足够量的区域特异性氟化的化合物。
多环芳烃,更重要的是,它们的氟化代谢物。因此,建议进行两方面的调查。(一)
区域特异性氟化多环芳烃及其代谢产物合成新方法的研究进展
以及对这些化合物的物理和生物学研究。氟化多环芳烃将用于2
合作研究的类型。一个涉及机械,理论和实验电荷分布
一项研究和另一项研究评价了氟代BcPh以及二氢二醇至DMA的代谢活化
烷化剂和比较研究BcPh。BcPh-DNA加合物被认为是难以捉摸的
与DNA修复有关,这是它们活性更高的原因。(B)DNA的比较物理和NMR研究
通过非活性6-F-BaP加合物改性的那些与通过高活性BaP二醇环氧化物改性的那些。数据
后者已在文献中提供。对于这些研究,由6-F-BaP二醇环氧化物修饰的DNA将
合成。从我们先前合成的6-F-BaP二氢二醇开始,非对映选择性合成了
将开发6-F-BaP二醇环氧化物(目前是前所未有的)。使用合成的二醇环氧化物,
将合成6-F-BaP的核苷-二醇环氧化物加合物,并将其掺入生物学上重要的
通过改良的固相DNA合成进行DNA序列测定。DNA位点特异性修饰的结构
6-F-BaP二醇环氧化物的反应将通过NMR进行研究。这是为了探讨F原子对DNA的影响
构象和用于与质子类似物的结构比较。这些研究将提供洞察力
转化为细微的结构差异,导致明显不同的生物反应。
项目成果
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{{ truncateString('BARBARA ZAJC', 18)}}的其他基金
Fluorine as a Probe in Polycyclic Aromatic Hydrocarbon Carcinogenesis Studies
氟作为多环芳烃致癌研究中的探针
- 批准号:
7574570 - 财政年份:
- 资助金额:
$ 15.95万 - 项目类别:
Fluorine as a Probe in Polycyclic Aromatic Hydrocarbon Carcinogenesis Studies
氟作为多环芳烃致癌研究中的探针
- 批准号:
7762774 - 财政年份:
- 资助金额:
$ 15.95万 - 项目类别:
Fluorine as a Probe in Polycyclic Aromatic Hydrocarbon Carcinogenesis Studies
氟作为多环芳烃致癌研究中的探针
- 批准号:
8035944 - 财政年份:
- 资助金额:
$ 15.95万 - 项目类别: