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Sulfur (VI) Fluoride Exchange (SuFEx) in Drug Discovery

Picture of Patrick Foster, speaker, in a lab setting
Patrick Foster
Graduate Student, Department of Chemistry
University of Georgia
iSTEM Building 2, Room 1218
Organic Seminar

The concept of click chemistry was first introduced by Sharpless and his coworkers in 20011 , with the copper-mediated azide-alkyne cycloaddition (CuAAC) being the first click reaction to be introduced. Although a robust and precise reaction, ligating azides with terminal alkynes to afford 1,4-disubstituted triazoles, CuAAC was inherently limited due to its utilization of toxic copper metal as well as its limiting requirement for pre-functionalization. Since then, click chemistry has evolved, driven by a high demand for biorthogonal reactions. In 2014, Sulfur Fluoride Exchange (SuFEx) chemistry was first introduced by Prof. Barry Sharpless and coworkers as a second generation click reaction. As an efficient water and oxygen-friendly biorthogonal metal-free click reaction that does not require pre-functionalization2 , SuFEx chemistry has a large range of utility, primarily in chemical biology and the field of drug discovery. While covalent drug discovery has traditionally focused on targeting cysteine, the amino acid is often absent in binding sites, which has led to the use of “beyond cysteine” protein labeling strategies.3 Due to recent advances in SuFEx chemistry, development of covalent chemical probes that site selectively engage certain amino acid residues (including tyrosine, lysine, histidine, serine, and threonine) in binding pockets was enabled. 4 While SuFEx has applications in several fields ranging from synthetic methodology to polymer and material sciences, recent developments in SuFEx chemistry as a discovery methodology probe for drug discovery for a variety of different biochemically relevant processes will be discussed. 5


[1] Kolb H., Finn MG., Sharpless KB. Angew. Chem., Int. Ed. 2001, 11, 2004-2021. 

[2] Dong J., Krasnova L., Finn MG., Sharpless KB. Angew. Chem. Int. Ed. 2014, 36, 9430-9448. 

[3] Huang H., Jones LH. 2023, 18, 725-735. 

[4] Zhang Z., Wu W., Tang W. Eur. J. Med. Chem. 2023, 257, 115502-115514. 

[5] Qin Z., Zhang K., He P., et al. Nat. Chem. 2023, 12, 1705-1714.

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