Synthesis and Studies of Site-Specific Carcinogen-DNA Lesions

位点特异性致癌物-DNA损伤的合成与研究

• 批准号: 8035941
• 负责人: MAHESH K LAKSHMAN
• 金额: $ 17.41万
• 依托单位: CITY COLLEGE OF NEW YORK
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8035941
• 关键词: 2' -deoxyadenosine; Address; Adenine; Affect; Alkylating Agents; Alkylation; Appearance; Aromatic Polycyclic Hydrocarbons; Bay Region; Benzo(a)pyrene; Biochemical; Biological; Biology; Carcinogens; Chemistry; Codon Nucleotides; Collaborations; Comparative Study; Complex; Cytosine; DNA; DNA Adducts; DNA Alkylation; DNA Binding; DNA Damage; DNA Sequence; DNA Structure; DNA lesion; Data; Databases; Deoxyadenosines; Deoxyguanosine; Development; Environment; Epoxy Compounds; Ethylene Oxide; Evaluation; Event; Funding; Glean; Glycols; Goals; Guanine; Housing; Human; Individual; Influentials; Investigation; Isomerism; Lesion; Malignant Neoplasms; Measurement; Mediating; Metabolic Activation; Metabolism; Metals; Methodology; Methods; Minor; Modification; Molecular; Molecular Conformation; Mutation; Nucleosides; Oregon; Outcome; Output; Palladium; Positioning Attribute; Process; Property; Proteins; Purines; Reaction; Research; Route; Scheme; Series; Site; Societies; Structure; System; Technology; Temperature; Testing; Time; Tumorigenicity; adduct; base; benzo(c)phenanthrene; carcinogenesis; chemical carcinogenesis; enantiomer; falls; flexibility; novel; prototype; purine; repaired; research study; response; single molecule; tumorigenesis; tumorigenic

Polycyclic aromatic hydrocarbons (PAHs) are ubiquitous in the environment and they pose a cancer threat to humans as they are products of activities in a modern society. Alternant bay and fjord region PAHs are metabolized to 4 isomeric diol epoxides that are potent DNA alkylating agents. Reaction of these diol epoxides with cellular DNA results in the formation of 16 nucleoside adducts; 8 isomers from deoxyadenosine (dA) and correspondingly 8 from deoxyguanosine (dG). The isomeric diol epoxides have markedly different tumorigenicities that implies differences in intracellular recognition, replication and repair the individual diol epoxide-nucleoside adducts. Thus, an understanding of the structural differences in the individual diol epoxide-DNA lesions in relation to the biological responses is expected to provide a better basis for understanding chemical carcinogenesis at the molecular level. The proposed studies are on two topologically different structural paradigms; the bay region represented by benzo[a]pyrene (BaP) and the fjord region represented by benzo[c]phenanthrene (BcPh) the DNA adducts of which are expected to elicit markedly different structural properties. One aim of the project is to complete delineation of novel, unequivocal synthesis of all diol epoxide-nucleoside adducts of these two PAHs. The methods that so evolve will potentially have general applicability for studies with any bay or fjord region PAH diol epoxide. The adducts will be incorporated into suitable DNA sequences (primarily human N-ras for the dA adducts and c-Ki-ras for the dG) for comparative studies within the individual sequence contexts. These include: 7m studies with normal and mismatched complementary strands, and temperature-dependent CD studies of the duplexes. The proposed synthesis encompasses ample flexibility to allow for the modification of any sequence or the incorporation of MeC adjacent to the dG adducts. Thus sequence context effects can also be probed. In-house collaboration will be the NMR structural evaluations of the modified duplexes. External collaborations are also planned for UvrABC repair experiments and single molecule studies on protein-DNA complexes. This concerted synthesis and structural evaluation is anticipated to contribute to a greater global understanding of the causative effects in PAH carcinogenesis.

多环芳烃（PAHS）在环境中无处不在，它们对癌症构成癌症威胁 人类是现代社会中活动的产物。替代湾和峡湾地区PAH是 代谢为有效的DNA烷基化剂的4种异构二醇环氧化物。这些二醇的反应 具有细胞DNA的环氧化物会导致形成16个核苷加合物。来自8个异构体 脱氧腺苷（DA），相应地来自脱氧鸟苷（DG）。异构二醇环氧化物具有 明显不同的肿瘤性意味着细胞内识别，复制和修复的差异 单个二醇环氧化物核苷加合物。因此，了解 与生物学反应有关的单个二醇环氧-DNA病变有望提供更好的 理解分子水平化学癌变的基础。拟议的研究是关于两个 拓扑不同的结构范例； Benzo [A] Pyrene（BAP）和 由苯并[c] emanththrene（BCPH）代表的峡湾区域预期会引起其DNA加合物 明显不同的结构特性。该项目的目的之一是完成小说的描述 这两个PAH的所有二醇环氧化物核苷加合物的明确合成。这样的方法 进化有可能对任何海湾或峡湾区PAH二醇环氧化的研究具有一般适用性。 加合物将被掺入合适的DNA序列（主要是DA加合物的人N-RAS 用于DG的C-KI-RAS）在单个序列环境中进行比较研究。其中包括：7m 对正常和不匹配的互补链的研究以及依赖温度的CD研究 双工。所提出的合成包含足够的灵活性，以允许修改任何 序列或与DG加合物相邻的MEC掺入。因此，序列上下文效应也可以 被探测。内部协作将是修改后的双工的NMR结构评估。外部的 还计划进行紫外线维修实验和蛋白质-DNA的单分子研究 复合物。预计这种一致的合成和结构评估将有助于更大的全球 了解PAH癌变中的致病作用。