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

项目摘要/摘要 该项目的中心目标是开发新的硫氟化物交换(SuFEx)反应，以构建 构建含SVI-F基序的小分子文库，并探讨其体内外功能。SuFEx是一个 用于产生含有SVI-F的不同化学结构的新的点击化学转换家族 基序，如-OSO2F(氟硫酸盐)和-SO2F(磺酰氟)。 在上一个资助期，我们建立了三个多用途的硫磺六号连接器：硫酰氟(SO2F2)， ESF和SOF4，其中SO2F2选择性地与- 酚基形成芳基氟硫酸盐。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 正电子发射断层扫描用放射性示踪剂。通过筛选基于芳基氟硫酸盐的文库，我们发现 细胞内脂结合蛋白的小分子共价修饰物(S)及其晚期平台 药物功能化。 基于这些发现，在下一个资金期，我们将开发新的转型以扩展 SuFEx转化库(目标1)。使用这些新的合成策略和我们已建立的SuFEx 工具，我们将设计和合成基于正电子的含胺探针的新的SVI-18F试剂 发射断层扫描(目标2)。最后，使用SuFEx化学，我们将准备小分子文库和 对它们进行筛选，以确定新的候选抗生素和抗癌化合物(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).