Bioorthogonal Generation and Use of Diazo-Compounds

描述(由申请人提供)：生物正交化学反应是研究各种生物途径如何运作的有力工具。这些转化需要平衡反应性，以便在不引起有害副反应的情况下实现预期的结果。叠氮官能团由于其与生物系统的兼容性以及易于合并而成为此类转化的极佳前体。最近，Raines小组开发了一种磷酸酯试剂，能够在温和的条件下在有机溶剂体系中将叠氮化合物转化为重氮化合物。第一个目标是合成一种相关的磷酸酯，它不需要有机溶剂就能发挥作用。试剂的水溶性和反应性将被系统地优化，以促进所需的转化，而不允许水或生物系统中存在的其他官能团发生反应。当第一个目标实现后，下一步将是探索得到的重氮化合物的反应性。最后，随着对反应性的彻底了解，测试将转移到生物环境中。高活性重氮化合物将用于生物分子的共价交联，以更好地了解它们的功能。这只是这种化学转化的许多有用应用之一。开发一种能够在生理条件下从生物相容的叠氮化合物中生成高活性重氮化合物的试剂将对化学生物学领域产生重大影响。 与公众健康相关：拟议的研究涉及开发一种水溶性试剂，能够在生理条件下将相对惰性的叠氮基转化为高活性的重氮基。这将作为化学生物学中理解各种生物过程如何运作的通用工具。此外，这种口径的转变将对合成化学产生重大影响，合成化学是一个总是在寻找选择性方法来生产反应官能团的领域。

DESCRIPTION (provided by applicant): Bioorthogonal chemical reactions are a powerful tool to investigate how various biological pathways operate. These transformations require a balance of reactivity in order to achieve the desired outcome without causing deleterious side reactions. The azide functionality has emerged as an excellent precursor for such transformations due to its compatibility with biological systems and the ease in which it can be incorporated. Recently, the Raines group developed a phosphinoester reagent that was capable of converting azides into diazo compounds under mild conditions in organic based solvent systems. The first goal is to synthesize a related phosphinoester that is able to function without the need of organic solvents. The water solubility and reactivity of the reagent will be systematically optimized to promote the desired transformation without allowing water or other functional groups present in biological systems to react. When the first goal has been realized, the next step will be to explore the reactivity of the resulting diazo compounds. Finally, with a thorough understanding of reactivity, the tests will be moved to a biological setting. The highly reactive diazo compounds will be used to covalently crosslink biomolecules to better understand their function. This is just one of many useful applications of this chemical transformation. The development of a reagent capable of producing highly reactive diazo compounds from biologically compatible azides under physiological conditions will have a significant impact on the field of chemical biology. PUBLIC HEALTH RELEVANCE: The proposed research involves developing a water soluble reagent capable of converting a relatively inert azide group into a highly reactive diazo group under physiological conditions. This will serve as a general tool in chemical biology to understand how various biological processes operate. In addition, a transformation of this caliber will have a significant impact in synthetic chemistry, a field always looking for selective methods to produce reactive functionality.