The Reversibility of DNA Alkylation by a Quinone Methide

有机和大分子化学项目支持马里兰大学学院园区的Steven E.Rokita教授，他建议探索化学和生物化学界面的研究，以发展对低分子试剂如何与其生物目标反应的预测性理解。这项研究将确定双链DNA中甲基醌加合物随时间的演化，并从根本上评估可逆性对大分子反应的影响。一种依赖于氧化捕获的新分析方法已经被开发出来，这样在双链DNA中形成的瞬时产物最终可能会受到以前只对单个核苷酸进行的同样的检查。由于该中间体的形成和反应以前已显示出对溶剂条件的敏感性，因此还将确定核苷酸序列在甲基苯醌再生中的作用。作为对DNA中电子转移研究的补充，进一步的研究将测量DNA作为电泳体(甲基苯醌)迁移的管道的能力，否则可能会被生化系统中相互竞争的亲核试剂所抑制。这一建议的结果应该为共价反应的可逆性如何深刻地影响形成DNA加合物的瞬时中间体的寿命和目标选择性提供一个概念基础。有机和大分子化学计划支持Steven E.Rokita教授，他将探索甲基苯醌与核酸反应的基本物理有机化学。Rokita教授发现，甲基苯醌可以与DNA反应，形成可逆的共价键。与DNA可逆的共价相互作用的概念已被认识多年，但直到最近才被认识到它在理解细胞对DNA损伤的反应方面的潜在意义。这项工作对于我们基本理解药物和毒素与DNA的相互作用，理解细胞对DNA损伤的反应的化学基础，以及最终设计针对许多人类疾病的DNA反应疗法具有重要意义。计划中的调查横跨化学和生物化学学科，吸引了许多各级学生，其中许多人在自然科学领域的代表性不足。将继续努力确保这些学生参与这项研究，并通过参加为少数族裔、高中教师和他们的学生服务的部门和大学计划，与他们的同事分享经验。

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.