Sulfur-Fluoride Exchange (SuFEx) has emerged as the new generation of click chemistry. We report here a SuFEx-enabled approach exploiting the “sleeping beauty” phenomenon of sulfur fluoride compounds in the context of the serendipitous discovery of selective covalent human neutrophil elastase (hNE) inhibitors. Evaluation of an ever-growing collection of SuFExable compounds toward various biological assays unexpectedly yielded a selective and covalent hNE inhibitor, benzene-1,2-disulfonyl fluoride. Derivatization of the initial hit led to a better agent, 2- triflyl benzenesulfonyl fluoride, itself made through a SuFEx trifluoromethylation process, with IC50 = 1.1 μM and ~200-fold selectivity over the homologous neutrophil serine protease, cathepsin G. The optimized probe only modified active hNE and not its denatured form, setting another example of the “sleeping beauty” phenomenon of sulfur fluoride capturing agents for the discovery of covalent medicines.
“Sleeping Beauty” Phenomenon: SuFEx-Enabled Discovery of Selective Covalent Inhibitors of Human Neutrophil Elastase
15 March 2019, Version 1
This content is a preprint and has not undergone peer review at the time of posting.
Zheng et al Sleeping Beauty 2019 SI