Sulfur(VI) Fluoride Exchange (SuFEx): new developments and biological applications

项目概要/摘要 该项目的中心目标是开发新的硫氟交换（SuFEx）反应，以构建 小分子文库的SVI-F基序，并探讨其在体外和体内功能。SuFEx是一个 用于产生带有SVI-F的不同化学结构的点击化学变换的新家族 基序，例如-OSO 2F（氟代硫酸盐）和-SO 2F（磺酰氟）。 在上一个融资期，我们建立了三种多功能SulfurVI连接器：硫酰氟（SO2 F2）， 乙烯磺酰氟（ESF）和四氟化硫（SOF 4），其中SO2 F2选择性地与- OH基团形成芳基氟代硫酸酯。基于这种转变，我们发明了极快的 将氟-18同位素引入生物活性小分子的氟交换反应 用于正电子发射断层扫描的放射性示踪剂。通过筛选基于芳基氟硫酸酯的文库，我们发现 用于细胞内脂质结合蛋白的小分子共价修饰剂和用于晚期脂质结合蛋白的平台 药物功能化 基于这些发现，在下一个资助期内，我们将开发新的改造，以扩大 SuFEx转换库（Aim 1）。使用这些新的合成策略和我们建立的SuFEx 工具，我们将设计和合成新的SVI-18F剂的基础上含胺探针的正电子 发射断层扫描（Aim 2）。最后，使用SuFEx化学，我们将制备小分子文库， 筛选它们以鉴定新的抗生素候选物和抗癌化合物（目标3）。

PROJECT SUMMARY/ABSTRACT The central goal of this project is to develop new sulfur fluoride exchange (SuFEx) reactions to construct small-molecule libraries containing the SVI-F motif and to explore their in vitro and in vivo functions. SuFEx is a new family of click chemistry transformations for generating diverse chemical structures bearing the SVI-F motif, such as -OSO2F (fluorosulfate) and -SO2F (sulfonyl fluoride). In the last funding period, we established three versatile SulfurVI connectors: sulfuryl fluoride (SO2F2), ethenesulfonyl fluoride (ESF) and thionyl tetrafluoride (SOF4), among which SO2F2 selectively reacts with the – OH group of phenols to form aryl fluorosulfates. Based on this transformation, we invented extremely fast fluoride exchange reactions to introduce the fluorine-18 isotope into biologically active small-molecule radiotracers for positron emission tomography. By screening aryl fluorosulfate-based libraries, we discovered small-molecule covalent modifiers for Intracellular Lipid Binding Protein(s) and a platform for the late-stage drug functionalization. Based on these discoveries, in the next funding period, we will develop new transformations to expand the SuFEx transformation repertory (Aim 1). Using these new synthetic strategies and our established SuFEx tools, we will design and synthesize new SVI-18F agents based on amine-containing probes for positron emission tomography (Aim 2). Finally, using SuFEx chemistry, we will prepare small-molecule libraries and screen them to identify new antibiotics candidates and anti-cancer compounds (Aim 3).