The Reversibility of DNA Alkylation by a Quinone Methide

醌甲基化物对 DNA 烷基化的可逆性

• 批准号: 0517498
• 负责人: Steven Rokita
• 金额: $ 38.2万
• 依托单位: University of Maryland, College Park
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-08-01 至 2009-07-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=0517498&HistoricalAwards=false
• 关键词: Reversibility; DNA; Alkylation; Quinone; Methide

The Organic and Macromolecular Chemistry Program supports Professor Steven E. Rokita at the University of Maryland- College Park who proposes to explore research at the interface of chemistry and biochemistry in order to develop a predictive understanding of how low molecular weight reagents react with their biological targets. The research will identify the time-dependent evolution of quinone methide adducts in duplex DNA and assess, in a fundamental manner, the impact of reversibility on macromolecular reaction. A new assay relying on oxidative trapping has been developed so that transient products formed in duplex DNA may finally receive the same scrutiny previously afforded to only individual nucleotides. The role of nucleotide sequence in quinone methide regeneration will also be determined since formation and reaction of this intermediate have previously shown sensitivity to solvent conditions. As a complement to studies on electron transfer in DNA, further investigations will measure the ability of DNA to act as a conduit for electrophile (quinone methide) migration that may otherwise be quenched by competing nucleophiles in a biochemical system. The results of this proposal should provide a conceptual foundation for how the reversibility of covalent reaction can profoundly affect the lifetime and target selectivity of transient intermediates forming DNA adducts.The Organic and Macromolecular Chemistry Program supports Professor Steven E. Rokita who will explore the fundamental physical organic chemistry underlying the reaction of quinone methides with nucleic acids. Professor Rokita has discovered that quinone methides can react with DNA to form reversible covalent bonds. The concept of reversible covalent interactions with DNA has been recognized for years but only recently has it been appreciated for its potential significance in understanding cellular responses to DNA damage. This work has significant implications for our basic understanding of the interactions of drugs and toxins with DNA, for understanding the chemical basis for cellular responses to DNA damage, and ultimately for designing DNA-reactive therapeutics for many human diseases. The planned investigations span the disciplines of chemistry and biochemistry and have attracted a number of students at all levels, many of which are underrepresented in science. Efforts will continue to ensure that such students participate in this research and share the experience with their colleagues by participating in departmental and college programs serving minorities, high school teachers and their students.

有机和高分子化学计划支持教授史蒂芬E。马里兰州大学帕克分校的Rokita博士建议探索化学和生物化学界面的研究，以预测低分子量试剂如何与其生物靶标反应。该研究将确定双链DNA中醌甲基化物加合物的时间依赖性演变，并从根本上评估可逆性对大分子反应的影响。已经开发了一种依赖于氧化捕获的新测定法，使得在双链体DNA中形成的瞬时产物可以最终接受先前仅提供给单个核苷酸的相同的仔细检查。也将确定醌甲基化物再生中核苷酸序列的作用，因为该中间体的形成和反应先前已显示出对溶剂条件的敏感性。作为对DNA中电子转移研究的补充，进一步的研究将测量DNA作为亲电体（醌甲基化物）迁移的管道的能力，否则可能会被生化系统中的竞争亲核体淬灭。这项建议的结果应提供一个概念基础，如何共价反应的可逆性可以深刻地影响寿命和目标选择性的瞬态中间体形成DNA加合物。他将探索醌甲基化物与核酸反应的基本物理有机化学。Rokita教授发现醌甲基化物可以与DNA反应形成可逆的共价键。与DNA的可逆共价相互作用的概念已经被认识多年，但直到最近才被理解为它在理解细胞对DNA损伤的反应中的潜在意义。这项工作对我们基本了解药物和毒素与DNA的相互作用，了解细胞对DNA损伤反应的化学基础，以及最终设计许多人类疾病的DNA反应性治疗方法具有重要意义。计划中的调查涵盖化学和生物化学学科，吸引了许多各级学生，其中许多人在科学方面的代表性不足。将继续努力确保这些学生参加这项研究，并通过参加为少数民族、高中教师及其学生服务的部门和大学方案与同事分享经验。