Quinone methide - based strategies for reversible modification, protection, and ligation of biological substrates and polymers

在这个由化学系化学结构、动态和机制B计划资助的项目中，佐治亚大学化学系的弗拉基米尔·波皮克教授正在开发利用光修改生物分子结构和材料结构的新方法。利用光引导生物分子的可逆衍生化方法，可以在时间和空间上控制它们的性质。这种化学方法的技术应用可能包括药物输送材料和蛋白质工程。该项目为学生提供合成化学、光化学和生物化学的跨学科训练。高中生正在通过佐治亚大学的Young Dawgs项目在Popik教授的实验室进行暑期实习，他们正在体验现代科学研究。在之前NSF的支持下，Popik教授开发了一类新的耐光性保护基团，并展示了光生邻苯二酚甲基化合物的Diels-Alder和Michael反应性。该策略结合了几个令人满意的特点：底物非常快速的释放，初始生色团的“漂白”，以及产生荧光标记或不同的颜色。光致变色部分为耐光性保护基团增加了内置定时器。Popik教授和他的团队正在设计和合成对长波光敏感的新的邻苯二酚甲基前体。此外，他们还在进一步研究邻苯二酚甲醚的形成机理和硫酚-甲基醌反应动力学的pH依赖性。半胱氨酸标记的pH控制允许这些残基在多个半胱氨酸底物上的选择性衍生化，因此他们将这些方法应用于不同条件下(pH、光、竞争亲核试剂)的蛋白质选择性衍生化，并检查蛋白质修饰的可逆性。在这种化学基础上，Popik教授还在探索将邻苯二酚甲基衍生物用作蛋白酶抑制剂的可行性。

In this project funded by the Chemical Structure, Dynamic & Mechanism B Program of the Chemistry Division, Professor Vladimir Popik of the Department of Chemistry at the University of Georgia is developing new approaches for modifying the structures of biological molecules and materials using light. Methods utilizing light-directed reversible derivatization of biological molecules would allow one to control their properties in time and in space. Technological applications of such chemical methods may include drug delivery materials and protein engineering. This project provides students with an interdisciplinary training at the interface of synthetic chemistry, photochemistry, and biochemistry. High school students are conducting summer internships in the laboratory of Professor Popik through the University of Georgia Young Dawgs Program, and they are experiencing modern scientific research. With previous NSF support Professor Popik developed a new family of photolabile protecting groups and demonstrated the Diels-Alder and Michael reactivity of photo-generated o-quinone methides. The strategy incorporates several desirable features: the very fast release of a substrate, "bleaching" of the initial chromophore, and the generation of a fluorescent marker or a different color. Photochromic moieties add a built-in timer for photolabile protecting groups. Professor Popik and his group are designing and synthesizing new o-quinone methide precursors sensitive to long wavelengths of light. Also, they are further studying the mechanism of o-quinone methide formation and the pH-dependence of the thiol- quinone methide reaction kinetics. The pH-control of cysteine labeling allows for selective derivatization of these residues in multi-cysteine substrates, so they are applying these methods to the selective derivatization of proteins under different conditions (pH, light, competing nucleophiles) and examining the reversibility of the protein modification. Based upon this chemistry, Professor Popik is also exploring the feasibility of using o-quinone methide derivatives as protease inhibitors.