DNA RADICAL KINETICS

该项目旨在测量DNA反应的速率常数， 自由基是抗癌剂形成的中间体， 导致DNA破坏的博莱霉素。 动力学测量将 通过采用动力学的激光闪光光解（LFP）方法完成 具有纳秒分辨率的光谱仪。 自由基将由已知的前体产生， 在LFP研究中很有用。 因为DNA自由基可以通过多种方式反应， 途径，与硫醇和一级反应的二级反应动力学， 顺序磷酸盐消除反应将直接测量， 水溶液，这些动力学值将作为基础 一个DNA自由基动力学尺度。 来自核糖和2- 由激光光解产生的脱氧核糖核苷， 其特征在于光谱，和这些反应的动力学 物种将通过直接观察衰变率来测量， 紫外线辐射核苷的C4'和C3'基团和2- 脱氧核苷和C4' DNA基团，其不含有用的 发色团，将通过使用背景报告物进行监测 产生紫外线可检测瞬变的反应。 β-磷酸根断裂机理的研究， 包括动力学同位素效应的研究，将集中在一般性 最近发现的协同消除途径。 因为许多癌症治疗的临床治疗方法涉及 通过自由基中间体破坏DNA的试剂的使用， 了解这些反应的动力学和机制 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.