Diversity oriented clicking delivers β-substituted alkenyl sulfonyl fluorides as covalent human neutrophil elastase inhibitors

Cheng, Yunfei, Li, Gencheng, Smedley, Christopher J, Giel, Marie-Claire, Kitamura, Seiya, Woehl, Jordan L, Bianco, Giulia, Forli, Stefano, Homer, Joshua A, Cappiello, John R, Wolan, Dennis W, Moses, John E, Sharpless, K Barry (September 2022) Diversity oriented clicking delivers β-substituted alkenyl sulfonyl fluorides as covalent human neutrophil elastase inhibitors. Proceedings of the National Academy of Sciences of USA, 119 (37). e2208540119. ISSN 0027-8424

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URL: https://www.ncbi.nlm.nih.gov/pubmed/36070343
DOI: 10.1073/pnas.2208540119


Diversity Oriented Clicking (DOC) is a discovery method geared toward the rapid synthesis of functional libraries. It combines the best attributes of both classical and modern click chemistries. DOC strategies center upon the chemical diversification of core "SuFExable" hubs-exemplified by 2-Substituted-Alkynyl-1-Sulfonyl Fluorides (SASFs)-enabling the modular assembly of compounds through multiple reaction pathways. We report here a range of stereoselective Michael-type addition pathways from SASF hubs including reactions with secondary amines, carboxylates, 1H-1,2,3-triazole, and halides. These high yielding conjugate addition pathways deliver unprecedented β-substituted alkenyl sulfonyl fluorides as single isomers with minimal purification, greatly enriching the repertoire of DOC and holding true to the fundamentals of modular click chemistry. Further, we demonstrate the potential for biological function - a key objective of click chemistry - of this family of SASF-derived molecules as covalent inhibitors of human neutrophil elastase.

Item Type: Paper
Subjects: chemistry > techniques > click chemistry
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > serine proteinase inhibitors
CSHL Authors:
Communities: CSHL labs > Moses lab
SWORD Depositor: CSHL Elements
Depositing User: CSHL Elements
Date: 13 September 2022
Date Deposited: 15 Sep 2022 20:49
Last Modified: 15 Sep 2022 20:49
URI: https://repository.cshl.edu/id/eprint/40717

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