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), -SO2F (sulfonyl
fluoride) and iminosulfur oxydifluorides. In the last seven years, we have established three
versatile SulfurVI connectors: sulfuryl fluoride (SO2F2), ethenesulfonyl fluoride (ESF), and thionyl
tetrafluoride (SOF4). SO2F2 selectively reacts with the – OH group of phenols to form aryl
fluorosulfates, whereas SOF4 selectively reacts with primary amines to form iminosulfur
oxydifluorides. Based on the aryl fluorosulfate chemistry, 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. Building upon the above exciting discoveries,
we will develop new transformations to expand the SuFEx transformation repertory and explore
the feasibility of expanding fluoride exchange reactions to stable phosphorous(V) hubs. We will
apply these new chemical transformations to construct screen libraries that can be used for rapid
hit-to-lead optimization and for the development of covalent inhibitors and to construct stable 18F
radiotracers for PET imaging.