DNA TOPOISOMERASE I TARGET INTERACTIONS OF CAMPTOTHECINS

描述（申请人的描述）：这五个研究目标- 一年的资助申请是探索DNA的分子水平的细节 抗癌药物喜树碱家族与拓扑酶I的相互作用 毒品 这项研究将在肯塔基州大学， 化学和药学院。喜树碱是一种实验性抗癌药物 以其新颖的作用机制而闻名的药物，抑制DNA- 加工酶拓扑异构酶I。 两种喜树碱（TPT和CPT-11）具有 最近获得了美国食品和药物管理局的临床批准， 1996年和1998年使用。该项目涉及实施各种 最先进的分析和生物物理方法，包括高场 核磁共振光谱（NMR），计算机分子建模， 高压液相色谱法，高灵敏度差示扫描 热分析和等温滴定量热法，光子相关 光谱学、激光诱导单光子和双光子荧光光谱学，以及 傅里叶变换质谱法。 这种高度互补的多样性 生物物理方法提供了一种用于获得详细的， 喜树碱的靶相互作用的生物物理学观点。的目的 该项目旨在了解分子水平上的相互作用细节， 临床相关的水溶性和亲脂性喜树碱， dsDNA和基因组DNA。形成的可裂解复合物的分子水平细节 dsDNA、拓扑异构酶I和喜树碱药物之间的关系。也 是药物在双链DNA中结合的结构基础， c o m plexes. 机制信息与结构-功能相关性 关于喜树碱对拓扑异构酶I功能的抑制， 追求。 本研究项目旨在定义学术研究 杨博士的计划谁是实现在第一个教师职位的意图- 美国的药学或医学研究型学院。

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.