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

硫（VI）氟化物交换（SuFEx）：新进展和生物应用

基本信息

批准号：
10557787
负责人：
KARL BARRY SHARPLESS
金额：
$ 44.38万
依托单位：
SCRIPPS RESEARCH INSTITUTE, THE
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-01-01 至 2024-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10557787
关键词：
Amines Anhydrides Anti-Bacterial Agents Antibiotics Antineoplastic Agents Bacterial Proteins Binding Proteins Biological Biological Process Biology Cancer Biology Cancer Diagnostics Carbon Cells Charge Chemical Structure Chemicals Chemistry Derivation procedure Development Enzyme Inhibitor Drugs Family Fluoride Ion Fluorides Fluorine Foundations Funding Goals Hydrogen Bonding Imidazole In Vitro Isotopes Libraries Lipid Binding Modification Multiple Bacterial Drug Resistance Pharmaceutical Preparations Phenols Positron-Emission Tomography Procedures Protein Family Proteins Reaction Reagent Reporting Side Sulfur Synthesis Chemistry Techniques Treatment Efficacy Validation anti-cancer aqueous breast cancer progression cancer proteomics cancer therapy clinical imaging design drug candidate fighting functional group in vivo inhibitor invention molecular assembly/self assembly multidisciplinary radiotracer screening small molecule small molecule inhibitor small molecule libraries tool

项目摘要

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).

项目概要/摘要该项目的中心目标是开发新的氟化硫交换（SuFEx）反应来构建 SuFEx 是一个包含 SVI-F 基序的小分子文库，并探索其体外和体内功能。新的点击化学转化系列，用于生成带有 SVI-F 的多种化学结构基序，例如-OSO2F（氟硫酸盐）和-SO2F（磺酰氟）。在上一个资助期间，我们建立了三种多功能的 SulfurVI 连接器：硫酰氟 (SO2F2)、乙烯磺酰氟 (ESF) 和四氟化亚硫酰 (SOF4)，其中 SO2F2 选择性地与 – 基于这种转变，我们发明了极快的酚类羟基形成芳基氟硫酸盐的方法。氟化物交换反应将氟 18 同位素引入生物活性小分子通过筛选基于芳基氟硫酸盐的库，我们发现了用于正电子发射断层扫描的放射性示踪剂。细胞内脂质结合蛋白的小分子共价修饰剂和后期平台药物功能化。基于这些发现，在下一个资助期内，我们将开发新的转型以扩大规模 SuFEx 转化库（目标 1）。工具，我们将设计和合成基于正电子含胺探针的新型SVI-18F试剂最后，使用 SuFEx 化学，我们将准备小分子库和筛选它们以确定新的候选抗生素和抗癌化合物（目标 3）。