DNA RADICAL KINETICS

该项目的目的是测量DNA反应的速率常数 自由基是由抗癌药物形成的中间体，如 导致DNA破坏的博莱霉素。动力学测量将是 通过使用动力学的激光闪光光解(LFP)方法完成 纳秒分辨率的分光计。 自由基将由已知的前体产生 在LFP研究中很有用。因为DNA自由基可以通过大量的 与硫醇的二级反应动力学和一级反应动力学。 级数磷酸盐消除反应将直接在 水溶液，这些动力学数值将作为基础 用于DNA自由基动力学标度。核糖和2-羧基的C_1‘自由基 激光光解产生的脱氧核糖核苷将是 光谱表征，以及这些化合物的反应动力学 物种将通过直接观察腐烂的速度来测量 紫外线的吸光度。核苷的C4‘和C3’自由基和2- 脱氧核苷和C4‘DNA自由基，不含有用的 发色团，将使用后台记者进行监控 产生可被紫外线检测到的瞬变的反应。 β-磷酸自由基裂解机理的研究， 包括动力学同位素效应的研究，将侧重于一般性 最近发现的一种协同消除途径。 因为许多癌症的临床治疗方法都涉及到 使用通过自由基中间体破坏DNA的试剂，是一件好事 对这些反应的动力学和机理的理解 物种对未来的药物开发将是重要的。

The project aims at measuring the rate constants of reactions of DNA radicals which are intermediates formed by anti-cancer agents such as bleomycin that result in DNA destruction. Kinetic measurements will be accomplished by laser flash photolysis (LFP) methods employing kinetic spectrometers with nanosecond resolution. The radicals will be produced from precursors that are known to be useful in LFP studies. Because DNA radicals can react by a number of pathways, the kinetics of second-order reactions with thiols and first- order phosphate elimination reactions will be measured directly in aqueous solutions, and these kinetic values will serve as the foundation for a DNA radical kinetic scale. C1' radicals from ribose and 2- deoxyribose nucleosides, produced by laser photolysis, will be characterized spectroscopically, and the kinetics of reactions of these species will be measured by direct observation of the rates of decay of the UV absorbances. C4' and C3' radicals of nucleosides and 2- deoxynucleoside and C4' DNA radicals, which do not contain useful chromophores, will be monitored by the use of background reporter reactions that produce UV-detectable transients. Studies of the mechanism of fragmentation of beta-phosphate radicals, including kinetic isotope effect studies, will focus on the generality of a concerted elimination pathway that was recently discovered. Because many clinical therapeutic approaches to cancer treatment involve the use of agents that destroy DNA via radical intermediates, a good understanding of the kinetic and mechanisms of reactions of these species will be important for future drug development.