DNA TOPOISOMERASE I TARGET INTERACTIONS OF CAMPTOTHECINS

描述(申请人描述)：这五个项目的研究目标- 年度拨款申请是为了探索DNA分子水平的细节 和抗癌喜树碱家族的拓扑异构酶I相互作用 毒品。这项研究将在肯塔基大学的 化学与药学学院。喜树碱是一种实验性抗癌药物 以其新的作用机制而闻名的试剂，抑制DNA- 加工酶拓扑异构酶I.两种喜树碱(TPT和CPT-11)有 最近获得了美国食品和药物管理局对临床的批准 在1996年和1998年使用。该项目涉及实施各种 包括高场在内的最先进的分析和生物物理方法 核磁共振波谱(核磁共振)、计算机分子模拟、 高压液相色谱、高灵敏度差示扫描 Ca L容量法和等温滴定量热法，光子关联 光谱学，激光诱导的单光子和双光子荧光光谱，以及 傅里叶变换质谱学。这种互补性很强的品种 生物物理方法提供了一种强大的方法来获得详细的、 喜树碱靶标相互作用的生物物理观点。的目的是 该项目是为了了解相互作用的分子水平细节。 临床相关的水溶性和亲脂性喜树碱 DsDNA和基因组DNA。形成的可切割络合物的分子水平细节 在dsDNA、拓扑异构酶I和喜树碱药物之间寻找。也可以 被研究是药物结合在dsDNA和可切割的结构基础 Com丛。机械信息与结构-功能相关性 关于喜树碱对拓扑异构酶I功能的抑制，将会是 被追捕。本研究项目旨在界定学术研究。 杨博士的计划，他致力于在第一个- 美国以研究为导向的药学或医学院。

DESCRIPTION (Applicant's Description): The research objective of this five- year grant application is to explore the molecular level details of the DNA and topoisornerase I interactions of the camptothecin family of anticancer drugs. The research will take place at University of Kentucky, Department of Chemistry and College of Pharmacy. Camptothecin is an experimental anticancer agent renowned for its novel mechanism of action, the inhibition of DNA- processing enzyme topoisomerase I. Two camptothecins (TPT and CPT-11) have recently gained the U.S. Food and Drug Administration's approval for clinical use in 1996 and 1998. The project involves the implementation of a variety of state-of-the-art analytical and biophysical methods including high field nuclear magnetic resonance spectroscopy (NMR), computer molecular modeling, high pressure liquid chromatography, high sensitivity differential scanning c a l o rimetry and isothermal titration calorimetry, photon correlation spectroscopy, laser-induced one- and two-photon fluorescence spectroscopy, and Fourier transform mass spectrometry. This variety of highly complementary biophysical methods provides a powerful approach for obtaining a detailed, biophysical view of the target interactions of the camptothecins. The aim of the project is to understand the molecular level details of the interactions of clinically relevant water-soluble as well as lipophilic camptothecins with dsDNA and genomic DNA. Molecular level details of cleavable complexes formed between dsDNA, topoisomerase I and camptothecin drugs will be sought. Also to be studied is the structural basis of drug binding in dsDNA and cleavable c o m plexes. Mechanistic information and structure-function correlations concerning the inhibition of topoisomerase I function by camptothecins will be pursued. This research project is intended to define the academic research program of Dr. Yang who is intent on achieving a faculty position in a first- rate research-oriented College of Pharmacy or Medicine in the United States.