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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).

项目总结/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，我们的发明速度极快将氟-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）。