Fluorine as a Probe in Polycyclic Aromatic Hydrocarbon Carcinogenesis Studies

许多环境中流行的多环芳烃(PAHs)在哺乳动物体内代谢 致癌物与细胞DNA发生反应，导致不利的生物和健康影响。这 通过多环芳烃到4个湾区二醇环氧化物的代谢活化而发生，这些环氧化物是DMA烷基化合物。这些 代谢产物与嘌呤碱基形成共价加合物，是这一过程引起的DMA损伤 这最终会导致突变和肿瘤的形成。氟的引入可以显著改变 多环芳烃及其代谢物的生物活性。例如，6-年的活动有所增加- 氟苯并[c]菲(6-F-BcPh)与苯并[c]菲(BcPh)的比较，而6-F-BcPh 氟苯并[a]芘(6-F-BaP)的活性显著降低。为了更好地理解 分子遗传水平上的构效关系，氟化多环芳烃及其化合物的研究 提出了代谢产物的概念。为此，拥有足够数量的区域特异性氟化是至关重要的。 多环芳烃，以及重要的是它们的氟化代谢物。因此，提出了两条调查路线。(A) 区域特异性氟化多环芳烃及其潜在代谢物合成新方法的开发 以及对这些化合物的物理和生物研究。氟化的多环芳烃将用于2 合作研究的类型。一种涉及机理、理论和实验的电荷分布 含氟BcPh和二氢二醇对二甲基亚胺代谢活性的研究及评价 烷基化试剂及其与所研究的BcPh的比较。BcPh-DNA加合物被认为是难以捉摸的 DNA修复是它们活性较高的原因。(B)DNA的比较物理和核磁共振研究 用不活性的6-F-BaP加合物与那些由高活性BaP二醇环氧化物修饰的加合物进行修饰。数据在 后者已经在文献中找到了。在这些研究中，经6-F-BaP二醇环氧化物修饰的DNA将 是人工合成的。从我们先前合成6-F-BaP二氢二醇开始，非对映选择性合成 将开发6-F-BaP二醇环氧化物(目前是前所未有的)。使用合成的二元醇环氧化物， 将合成6-F-BaP的核苷二醇环氧化物加合物，并将其引入到具有重要生物学意义的 通过改进的固相DNA合成进行DNA序列测定。DNA定点修饰的结构 通过6-F-BaP对二元醇环氧化物进行了核磁共振研究。这是为了探索F原子对DNA的影响 用于构象和结构与原类似物的比较。这些研究将提供洞察力 细微的结构差异导致了明显不同的生物反应。

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.