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）在环境中普遍存在，它们对人类构成癌症威胁。 人类是现代社会活动的产物。交替海湾和峡湾地区的多环芳烃是 代谢成4种异构二醇环氧化物，它们是有效的DNA烷基化剂。这些二醇的反应 与细胞DNA的环氧化物导致形成16种核苷加合物; 8种异构体， 脱氧腺苷（dA）和相应的脱氧鸟苷（dG）的8个。异构二醇环氧化物具有 显著不同的致瘤性，意味着细胞内识别、复制和修复的差异 单独的二醇环氧化物-核苷加合物。因此，了解结构差异， 个体二醇环氧-DNA损伤与生物学反应的关系预期提供更好的 在分子水平上理解化学致癌作用的基础。拟议的研究涉及两项 拓扑结构不同的结构范例;以苯并[a]芘（BaP）为代表的海湾地区和 以苯并[c]菲（BcPh）为代表的峡湾区域，其DNA加合物预计会引发 明显不同的结构特性。该项目的目的之一是完成小说的描绘， 这两种多环芳烃的所有二醇环氧化物-核苷加合物的明确合成。这种方法， evolve将可能对任何海湾或峡湾地区PAH二醇环氧化物的研究具有普遍适用性。 将加合物掺入合适的DNA序列中（对于dA加合物，主要是人N-ras 和c-Ki-ras用于dG）用于在单个序列背景内的比较研究。其中：7 m 正常和错配互补链的研究，以及温度依赖性CD研究， 双链体。所提出的合成包括足够的灵活性，以允许对任何合成物进行修饰。 序列或MeC邻近dG加合物的掺入。因此，序列上下文效应也可以 被探测。内部合作将是对修饰的双链体进行NMR结构评价。外部 还计划在UvrABC修复实验和蛋白质-DNA单分子研究方面进行合作 配合物这种协调一致的综合和结构评价预计将有助于更大的全球 了解PAH致癌作用的原因。