Chemoselective Preparation of Clickable Aryl Sulfonyl Fluoride Monomers: A Toolbox of Highly Functionalized Intermediates for Chemical Biology Probe Synthesis

Abstract

Sulfonyl fluoride (SF)-based activity probes have become important tools in chemical biology. Herein, exploiting the relative chemical stability of SF to carry out a number of unprecedented SF-sparing functional group manipulations, we report the chemoselective synthesis of a toolbox of highly functionalized aryl SF monomers that we used to quickly prepare SF chemical biology probes. In addition to SF, the monomers bear an embedded click handle (a terminal alkyne that can perform copper(I)-mediated azide-alkyne cycloaddition). The monomers can be used either as fragments to prepare clickable SF analogues of drugs (biologically active compounds) bearing an aryl ring or, alternatively, attached to drugs as minimalist clickable aryl SF substituents.

SuFEx-enabled, agnostic discovery of covalent inhibitors of human neutrophil elastase

“…click chemistry | SuFEx | agnostic | covalent inhibitor | elastase S ulfur fluoride exchange (SuFEx)-the new-generation click chemistry, since first introduced in 2014 (1), has quickly found diverse applications across an array of fields (DOI: 10.1039/C8CS00960K), including chemical synthesis (2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12), material science (13)(14)(15)(16)(17)(18)(19), chemical biology (20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32), and drug discovery (33,34). SuFEx creates robust intermolecular links between modules.…”

“…In the context of selective in vitro or in vivo covalent capture of proteins by compounds containing a S-F bond that can undergo SuFEx reaction (i.e., SuFExable compounds), examples are rapidly accumulating (20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31). However, we are still far from making strong a priori inferences about the various factors that might relate to a given capture's occurrence.…”

From Differential Stains to Next Generation Physiology: Chemical Probes to Visualize Bacterial Cell Structure and Physiology

“…Another tantalizing prospect is the direct installation of chemical handles for click chemistry onto drugs or other bioactive molecules [119], which can then be visualized through subsequent bio-orthogonal conjugation with a fluorophore or other observable feature; thus, the strategy rapidly generates a new chemical probe [120]. Indeed, click chemistry itself (including SuFEx chemistry) is emerging not only as a means of bio-orthogonal probe visualization, but also as a tool in the synthesis and late-stage functionalization of new biological probes [18,[121][122][123].…”

“Sleeping Beauty” Phenomenon: SuFEx-Enabled Discovery of Selective Covalent Inhibitors of Human Neutrophil Elastase

“…Sulfur fluoride exchange (SuFEx)-the new generation click chemistry, since first introduced in 2014 (1), has quickly found diverse applications across an array of fields including chemical synthesis (2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12), material science (13)(14)(15)(16)(17)(18)(19), chemical biology (20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31), and drug discovery (32,33).…”

“…In the context of selective in vitro or in vivo covalent capture of proteins by SuFExable * compounds, examples are accumulating rapidly (20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31), but we are still reluctant to make strong a priori inferences about the factors which determine a given capture's occurrence. This said, there is one remarkable fact shared by all SuFEx-based protein captures that the probes' special S-F links are among the most demure electrophiles known † (1, [34][35][36][37][38].…”