Photoswitchable Analogs of Natural Enediyne Antibiotics

天然烯二炔抗生素的光开关类似物

基本信息

批准号：
6952956
负责人：
THOMAS H. KINSTLE
金额：
$ 20.85万
依托单位：
BOWLING GREEN STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2001
资助国家：
美国
起止时间：
2001-08-01 至 2009-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/6952956
关键词：
DNA binding protein antineoplastic antibiotics azo compounds carbonyl compound chemical cleavage cyclization drug design /synthesis /production enzyme activity ketones nuclease photoactivation ruthenium

项目摘要

DESCRIPTION (provided by applicant): This project describes the development of photoswitchable enediynes, which are stable in the dark but convert into very reactive cyclic enediyne compounds upon irradiation with light. The latter then undergoes facile cycloaromatization to produce a p-benzyne diradical. The photo-induced formation of highly strained enediynes opens the opportunity for the spatial and temporal control of the generation of the cytotoxic p-benzyne and direct spectroscopic observation of its reactions. The photoswitchable enediynes will be used to study the reversibility of the Bergman cyclization, as well as the feasibility of the enediyne reactivity control by shifting the position of keto-enol equilibrium. The photo-precursor of the azo-analog of the activated neocarzinostatin chromophore will be prepared to explore the azo-Myers cycloaromatization. The photoswitchable enediynes suitable for the two-photon activation will be developed as well. The non-resonant two-photon excitation (2PE) allows for the use of light in a so-called "phototherapeutic window", a region of relative tissue transparency between 650 and 950 nm, as well as conduct irradiation through a UV-Vis opaque media. In addition, the 2PE provides an opportunity for three-dimensional control of enediyne reactivity. To achieve these goals, photoprecursors of highly strained nine-membered ring enediynes, as well as cyclic enediynes incorporating additional endocyclic double bonds, will be synthesized. The photoswitchable enediynes containing extended chains of conjugation with D-A-D and D-pi-A-pi-D structural motifs will be used for the 2PE experiments. The in-situ generation of reactive enediynes is based on two strategies: 1) the photochemical ring contraction of eleven-membered ring enediynes and 2) the in situ photochemical generation of pi-components of the enediyne conjugated system. The successful completion of this project will supply new tools for exploring the mode of action of natural antitumor antibiotics. Photoactivatable enediynes can serve as a basis for the development of new photoactivatable enediyne antibiotics and 3-D selective photonucleases.

描述（由申请人提供）：该项目描述了可拍照的EneDiynes的发展，在黑暗中稳定，但在光线照射后转化为非常反应性的循环Enediyne化合物。然后，后者经历了易于的环磁瘤化，以产生p-benzyne diradical。光诱导的高度紧张的表现形成为细胞毒性p-苯甲体生成的空间和时间控制和对其反应的直接光谱观察提供了机会。可通过照片开关的EneDiynes将用于研究伯格曼环化的可逆性，以及通过移动酮 - 烯醇平衡的位置来控制Enediyne反应性控制的可行性。活化的Neocarzinostatin发色团的Azo-Analog的照相前体将准备探索Azo-Myers环氧化型环化学。还将开发适合两光激活的可照相带动性的EneDiynes。非共振的两光激发（2PE）允许在所谓的“光疗窗口”中使用光，这是650至950 nm之间相对组织透明度的区域，并通过UV-VIS不透明介质进行辐照。此外，2PE为三维控制Enediyne反应性提供了机会。为了实现这些目标，将合成高度紧张的九元环的光摄影器，以及结合其他内猫双键的环状Enediynes。可将照片开关的EneDiynes包含与D-A-D和D-PI-A-PI-D结构基序共轭的扩展链，将用于2PE实验。反应性的原位产生基于两种策略：1）十一元环的光化环收缩和2）原位光化学的pi components的pi components的原位光化学生成。该项目的成功完成将为探索天然抗肿瘤抗生素的作用方式提供新的工具。可光活化的EneDiynes可以作为开发新的光活化ENEDIYNE抗生素和3-D选择性光核酸的基础。