Oxygen-linked Phenol-DNA Adducts

描述（由申请人提供）：苯酚是人类环境中普遍存在的成分。本研究计划的主要目标是确定控制其致癌性和抗癌性之间平衡的化学和生化过程。核心假设是，酚类化合物可以形成DNA损伤，在嘌呤核苷的C8位置含有o -连接的芳基，这可能与癌症病因有关。为了开发解决这些问题所需的化学工具，本提案的具体目标是：(1)开发一种C8修饰的酚取代嘌呤核苷类似物的合成方法；(2)合成含有o -连接苯酚加合物的寡核苷酸，并测定其稳定性；(3)建立一种检测o链苯酚加合物的分析方法，并表征苯酚活化与加合物形成之间的关系。这项研究的结果对于评估酚类物质在癌症中的作用、开发暴露生物标志物、制定环境监管指南以及建立基于酚类物质的化学预防的重要概念具有重要意义。该候选人将于2004年7月成为明尼苏达大学药物化学助理教授，并在癌症中心任职。她拥有麻省理工学院化学博士学位，主要研究有机合成。作为美国癌症协会的博士后研究员，他的研究重点转向了致癌和化学预防。通过参与合作研究、指导学生、撰写拨款、部门服务、教学和科学会议，为候选人提供了多种专业发展机会。近期的职业目标包括过渡到一个独立的教师职位，并启动一个基于合成有机化学与致癌机制研究结合的研究项目。长期的职业目标是培养一个严谨活跃的研究小组，研究环境因素引起的癌症，致癌物质暴露的诊断工具，以及预防方法。研究职业发展计划是一个分阶段的项目——一个旨在加强候选人癌症研究技能和专业发展的指导阶段，一个将研究过渡到独立实验室的独立阶段。研究环境提供了教师专业知识和主要仪器，非常适合所提出的工作。

DESCRIPTION (provided by applicant): Phenols are ubiquitous components of the human environment. The broad objectives of this research program are to determine the chemical and biochemical processes controlling the balance between their carcinogenic and anticarcinogenic properties. The central hypothesis is that phenolic compounds can form DNA lesions, containing an O-linked aryl group at the C8 position of purine nucleosides, which may contribute to cancer etiology. To develop the chemical tools needed to address these issues, the specific aims of this proposal are: (1) Develop a synthetic approach to phenol-substituted purine nucleoside analogs modified at C8; (2) Synthesize oligonucleotides containing O-linked phenol adducts and determine their stability; and (3) Develop an analytical method for the detection of O-linked phenol adducts and characterize the relationship between phenol activation and adduct formation. The results of this study can be important for evaluating the role of phenols in cancer, developing biomarkers of exposure, generating environmental regulatory guidelines, and establishing concepts important for phenol-based chemoprevention. The candidate will become (July, 2004) an assistant professor of Medicinal Chemistry at the University of Minnesota with an appointment in the Cancer Center. She holds a Ph.D. in Chemistry from MIT, where her research focused on organic synthesis. As an American Cancer Society postdoctoral fellow, the focus shifted to carcinogenesis and chemoprevention. The candidate has been presented with diverse opportunities for professional development through participation in collaborative research, supervising students, grant-writing, departmental service, teaching, and scientific conferences. Immediate career goals include transitioning to an independent faculty position and initiating a research program based on the union of synthetic organic chemistry with the study of carcinogenic mechanisms. The long-term career objective is to foster a rigorously active research group investigating initiation of cancer by environmental agents, diagnostic tools for carcinogen exposure, and prevention methods. The research career development plan is a phased program - a mentored period designed to strengthen the candidate's cancer research skills and professional development, and an independent phase to transition the research to the independent laboratory. The research environment presents faculty expertise and major instrumentation ideally suited for the proposed work.