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).
The synthetic strategies developed in this project will help pave the way to invent ultrafast techniques to prepare radiotracers for positron emission tomography to be used in clinical imaging. From our screening efforts, we anticipate finding small-molecule inhibitors that may have the potential to be further developed into new antibiotics to fight against multi-drug resistant bacteria and anti-cancer drug candidates.
|Liu, Zilei; Li, Jie; Li, Suhua et al. (2018) SuFEx Click Chemistry Enabled Late-Stage Drug Functionalization. J Am Chem Soc 140:2919-2925|
|Mortenson, David E; Brighty, Gabriel J; Plate, Lars et al. (2018) ""Inverse Drug Discovery"" Strategy To Identify Proteins That Are Targeted by Latent Electrophiles As Exemplified by Aryl Fluorosulfates. J Am Chem Soc 140:200-210|
|Gao, Bing; Li, Suhua; Wu, Peng et al. (2018) SuFEx Chemistry of Thionyl Tetrafluoride (SOF4 ) with Organolithium Nucleophiles: Synthesis of Sulfonimidoyl Fluorides, Sulfoximines, Sulfonimidamides, and Sulfonimidates. Angew Chem Int Ed Engl 57:1939-1943|
|Gahtory, Digvijay; Sen, Rickdeb; Pujari, Sidharam et al. (2018) Quantitative and Orthogonal Formation and Reactivity of SuFEx Platforms. Chemistry 24:10550-10556|
|Zha, Gao-Feng; Zheng, Qinheng; Leng, Jing et al. (2017) Palladium-Catalyzed Fluorosulfonylvinylation of Organic Iodides. Angew Chem Int Ed Engl 56:4849-4852|
|Li, Suhua; Wu, Peng; Moses, John E et al. (2017) Multidimensional SuFEx Click Chemistry: Sequential Sulfur(VI) Fluoride Exchange Connections of Diverse Modules Launched From An SOF4 Hub. Angew Chem Int Ed Engl 56:2903-2908|
|Chen, Wentao; Dong, Jiajia; Plate, Lars et al. (2016) Arylfluorosulfates Inactivate Intracellular Lipid Binding Protein(s) through Chemoselective SuFEx Reaction with a Binding Site Tyr Residue. J Am Chem Soc 138:7353-64|
|Zheng, Qinheng; Dong, Jiajia; Sharpless, K Barry (2016) Ethenesulfonyl Fluoride (ESF): An On-Water Procedure for the Kilogram-Scale Preparation. J Org Chem 81:11360-11362|
|Qin, Hua-Li; Zheng, Qinheng; Bare, Grant A L et al. (2016) A Heck-Matsuda Process for the Synthesis of ?-Arylethenesulfonyl Fluorides: Selectively Addressable Bis-electrophiles for SuFEx Click Chemistry. Angew Chem Int Ed Engl 55:14155-14158|
|Zhang, Enxuan; Tang, Jiaze; Li, Suhua et al. (2016) Chemoselective Synthesis of Polysubstituted Pyridines from Heteroaryl Fluorosulfates. Chemistry 22:5692-7|